Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof

ABSTRACT

Compounds of Formula (IA) 
                         
wherein R 1 , R 2 , R 3 , R 4  and R 5  are as defined herein for Formula (IA), or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/944,615, filedSep. 17, 2004, which is a continuation of U.S. patent Ser. No.10/394,303, which claims benefit of U.S. Ser. No. 60/367,758, filed Mar.26, 2002; U.S. Ser. No. 60/431,817, filed Dec. 9, 2002; and U.S. Ser.No. 60/442,404, filed Jan. 24, 2003, each application of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to glucocorticoid mimetics or ligands,methods of making such compounds, their use in pharmaceuticalcompositions, and their use in modulating the glucocorticoid receptorfunction, treating disease-states or conditions mediated by theglucocorticoid receptor function in a patient in need of such treatment,and other uses.

BACKGROUND OF THE INVENTION

Glucocorticoids, a class of corticosteroids, are endogenous hormoneswith profound effects on the immune system and multiple organ systems.They suppress a variety of immune and inflammatory functions byinhibition of inflammatory cytokines such as IL-1, IL-2, IL-6, and TNF,inhibition of arachidonic acid metabolites including prostaglandins andleukotrienes, depletion of T-lymphocytes, and reduction of theexpression of adhesion molecules on endothelial cells (P. J. Barnes,Clin. Sci., 1998, 94, pp. 557-572; P. J. Barnes et al., TrendsPharmacol. Sci., 1993, 14, pp. 436-441). In addition to these effects,glucocorticoids stimulate glucose production in the liver and catabolismof proteins, play a role in electrolyte and water balance, reducecalcium absorption, and inhibit osteoblast function.

The anti-inflammatory and immune suppressive activities of endogenousglucocorticoids have stimulated the development of syntheticglucocorticoid derivatives including dexamethasone, prednisone, andprednisolone (L. Parente, Glucocorticoids, N.J. Goulding and R.J.Flowers (eds.), Boston: Birkhauser, 2001, pp. 35-54). These have foundwide use in the treatment of inflammatory, immune, and allergicdisorders including rheumatic diseases such as rheumatoid arthritis,juvenile arthritis, and ankylosing spondylitis, dermatological diseasesincluding psoriasis and pemphigus, allergic disorders including allergicrhinitis, atopic dermatitis, and contact dermatitis, pulmonaryconditions including asthma and chronic obstructive pulmonary disease(COPD), and other immune and inflammatory diseases including Crohndisease, ulcerative colitis, systemic lupus erythematosus, autoimmunechronic active hepatitis, osteoarthritis, tendonitis, and bursitis (J.Toogood, Glucocorticoids, N.J. Goulding and R.J. Flowers (eds.), Boston:Birkhauser, 2001, pp. 161-174). They have also been used to help preventrejection in organ transplantation.

Unfortunately, in addition to the desired therapeutic effects ofglucocorticoids, their use is associated with a number of adverse sideeffects, some of which can be severe and life-threatening. These includealterations in fluid and electrolyte balance, edema, weight gain,hypertension, muscle weakness, development or aggravation of diabetesmellitus, and osteoporosis. Therefore, a compound that exhibited areduced side effect profile while maintaining the potentanti-inflammatory effects would be particularly desirable especiallywhen treating a chronic disease.

The effects of glucocorticoids are mediated at the cellular level by theglucocorticoid receptor (R. H. Oakley and J. Cidlowski, Glucocorticoids,N.J. Goulding and R.J. Flowers (eds.), Boston: Birkhauser, 2001, pp.55-80). The glucocorticoid receptor is a member of a class ofstructurally related intracellular receptors that when coupled with aligand can function as a transcription factor that affects geneexpression (R. M. Evans, Science, 1988, 240, pp. 889-895). Other membersof the family of steroid receptors include the mineralocorticoid,progesterone, estrogen, and androgen receptors. In addition to theeffects mentioned above for glucocorticoids, hormones that act on thisreceptor family have a profound influence on body homeostasis, mineralmetabolism, the stress response, and development of sexualcharacteristics. Glucocorticoids, N.J. Goulding and R.J. Flowers (eds.),Boston: Birkhauser, 2001, is hereby incorporated by reference in itsentirety to better describe the state of the art.

A molecular mechanism which accounts for the beneficialanti-inflammatory effects and the undesired side effects has beenproposed (e.g., S. Heck et al., EMBO J, 1994, 17, pp. 4087-4095; H. M.Reichardt et al., Cell, 1998, 93, pp. 531-541; F. Tronche et al., Curr.Opin. in Genetics and Dev., 1998, 8, pp. 532-538). Many of the metabolicand cardiovascular side effects are thought to be the result of aprocess called transactivation. In transactivation, the translocation ofthe ligand-bound glucocorticoid receptor to the nucleus is followed bybinding to glucocorticoid response elements (GREs) in the promoterregion of side effect-associated genes, for example, phosphoenolpyruvatecarboxy kinase (PEPCK), in the case of increased glucose production. Theresult is an increased transcription rate of these genes which isbelieved to result, ultimately, in the observed side effects. Theanti-inflammatory effects are thought to be due to a process calledtransrepression. In general, transrepression is a process independent ofDNA binding that results from inhibition of NF-kB and AP-1-mediatedpathways, leading to down regulation of many inflammatory and immunemediators. Additionally, it is believed that a number of the observedside effects may be due to the cross-reactivity of the currentlyavailable glucocorticoids with other steroid receptors, particularly themineralocorticoid and progesterone receptors.

Thus, it may be possible to discover ligands for the glucocorticoidreceptor that are highly selective and, upon binding, can dissociate thetransactivation and transrepression pathways, providing therapeuticagents with a reduced side effect profile. Assay systems to determineeffects on transactivation and transrepression have been described(e.g., C. M. Bamberger and H. M. Schulte, Eur. J. Clin. Invest., 2000,30 (suppl. 3), pp. 6-9). Selectivity for the glucocorticoid receptor maybe determined by comparing the binding affinity for this receptor withthat of other steroid family receptors including those mentioned above.

Glucocorticoids also stimulate the production of glucose in the liver bya process called gluconeogenesis and it is believed that this process ismediated by transactivation events. Increased glucose production canexacerbate type II diabetes, therefore a compound that selectivityinhibited glucocorticoid mediated glucose production may havetherapeutic utility in this indication (J. E. Freidman et al., J. Biol.Chem., 1997, 272, pp. 31475-31481).

Novel ligands for the glucocorticoid receptor have been described in thescientific and patent literature. For example, PCT InternationalPublication No. WO 99/33786 discloses triphenylpropanamide compoundswith potential use in treating inflammatory diseases. PCT InternationalPublication No. WO 00/66522 describes non-steroidal compounds asselective modulators of the glucocorticoid receptor potentially usefulin treating metabolic and inflammatory diseases. PCT InternationalPublication No. WO 99/41256 describes tetracyclic modulators of theglucocorticoid receptor potentially useful in treating immune,autoimmune, and inflammatory diseases. U.S. Pat. No. 5,688,810 describesvarious non-steroidal compounds as modulators of glucocorticoid andother steroid receptors. PCT International Publication No. WO 99/63976describes a non-steroidal, liver-selective glucocorticoid antagonistpotentially useful in the treatment of diabetes. PCT InternationalPublication No. WO 00/32584 discloses non-steroidal compounds havinganti-inflammatory activity with dissociation between anti-inflammatoryand metabolic effects. PCT International Publication No. WO 98/54159describes non-steroidal cyclically substituted acylanilides with mixedgestagen and androgen activity. U.S. Pat. No. 4,880,839 describesacylanilides having progestational activity and EP 253503 disclosesacylanilides with antiandrogenic properties. PCT InternationalPublication No. WO 97/27852 describes amides that are inhibitors offarnesyl-protein transferase.

A compound that is found to interact with the glucocorticoid receptor ina binding assay could be an agonist or an antagonist. The agonistproperties of the compound could be evaluated in the transactivation ortransrepression assays described above. Given the efficacy demonstratedby available glucocorticoid drugs in inflammatory and immune diseasesand their adverse side effects, there remains a need for novelglucocorticoid receptor agonists with selectivity over other members ofthe steroid receptor family and a dissociation of the transactivationand transrepression activities. Alternatively, the compound may be foundto have antagonist activity. As mentioned above, glucocorticoidsstimulate glucose production in the liver. Increased glucose productioninduced by glucocorticoid excess can exacerbate existing diabetes, ortrigger latent diabetes. Thus a ligand for the glucocorticoid receptorthat is found to be an antagonist may be useful, inter alia, fortreating or preventing diabetes.

SUMMARY OF THE INVENTION

The instant invention is directed to compounds of Formula (IA)

wherein:

-   R¹ is an aryl or heteroaryl group, each optionally independently    substituted with one to three substituent groups,    -   wherein each substituent group of R¹ is independently C₁-C₅        alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl,        heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy,        C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅        alkanoyloxy, C₁-C₅ alkanoyl, aroyl, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy,        C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy,        C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅        alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl,        C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano,        trifluoromethyl, trifluoromethoxy, nitro, or amino wherein the        nitrogen atom is optionally independently mono- or        di-substituted by C₁-C₅ alkyl or aryl; or ureido wherein either        nitrogen atom is optionally independently substituted with C₁-C₅        alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally        oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R¹ is optionally            independently substituted with one to three substituent            groups selected from methyl, methoxy, halogen, hydroxy, oxo,            cyano, or amino,-   R² and R³ are each independently hydrogen or C₁-C₅ alkyl, or R² and    R³ together with the carbon atom they are commonly attached to form    a C₃-C₈ spiro cycloalkyl ring;-   R⁴ is C₁-C₅ alkyl, C₂-C₅ alkenyl, or C₂-C₅ alkynyl, each optionally    independently substituted with one to three substituent groups,    -   wherein each substituent group of R⁴ is independently C₁-C₃        alkyl, hydroxy, halogen, amino, or oxo; and-   R⁵ is a heteroaryl group optionally independently substituted with    one to three substituent groups,    -   wherein each substituent group of R⁵ is independently C₁-C₅        alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl,        heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy,        C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅        alkanoyloxy, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅        alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅        alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅        alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl,        C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano,        trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro,        or amino wherein the nitrogen atom is optionally independently        mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either        nitrogen atom is optionally independently substituted with C₁-C₅        alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally        oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R⁵ is optionally            independently substituted with one to three substituent            groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen,            hydroxy, oxo, cyano, amino, or trifluoromethyl,            or a tautomer, prodrug, solvate, or salt thereof.

Another aspect of the invention includes compounds of Formula (IA),wherein:

-   R¹ is thienyl, phenyl, naphthyl, dihydrobenzofuranyl, benzofuranyl,    chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl,    benzothienyl, benzodioxolanyl, dihydrobenzoxazolyl, benzoxazolyl,    benzisoxazolyl, benzpyrazolyl, benzimidazolyl, quinolinyl,    pyridinyl, pyrimidinyl, or pyrazinyl, each optionally independently    substituted with one to three substituent groups,    -   wherein each substituent group of R¹ is independently C₁-C₃        alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃        alkenyloxy, C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃        alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl,        trifluoromethoxy, nitro, or C₁-C₃ alkylthio wherein the sulfur        atom is optionally oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R¹ is optionally            independently substituted with a substituent group selected            from methyl, methoxy, halogen, hydroxy, oxo, cyano, or            amino;-   R² and R³ are each independently hydrogen or C₁-C₃ alkyl, or R² and    R³ together with the carbon atom they are commonly attached to form    a C₃-C₆ spiro cycloalkyl ring;-   R⁴ is CH₂; and-   R⁵ is an imidazolyl, pyridyl, indolyl, azaindolyl, diazaindolyl,    benzofuranyl, furanopyridinyl, furanopyrimidinyl, benzothienyl,    thienopyridinyl, thienopyrimidinyl, benzoxazolyl, oxazolopyridinyl,    benzothiazolyl, thiazolopyridinyl, benzimidazolyl,    imidazolopyridinyl, quinolinyl, or isoquinolinyl group, each    optionally independently substituted with one to three substituent    groups,    -   wherein each substituent group of R⁵ is independently C₁-C₃        alkyl, C₂-C₃ alkenyl, phenyl, C₁-C₃ alkoxy, methoxycarbonyl,        aminocarbonyl, C₁-C₃ alkylaminocarbonyl, C₁-C₃        dialkylaminocarbonyl, heterocyclylcarbonyl, fluoro, chloro,        bromo, cyano, trifluoromethyl, or C₁-C₃ alkylthio wherein the        sulfur atom is optionally oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R⁵ is optionally            independently substituted with a substituent group selected            from methyl, methoxy, fluoro, chloro, bromo, oxo, or            trifluoromethyl,            or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compounds of Formula (IA),wherein:

-   R¹ is thienyl, phenyl, naphthyl, pyridyl, chromanyl,    dihydrobenzofuranyl, or benzofuranyl, each optionally independently    substituted with one or two substituent groups,    -   wherein each substituent group of R¹ is independently methyl,        ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy,        trifluoromethyl, trifluoromethoxy, or cyano;-   R² and R³ are each independently methyl, or R² and R³ together with    the carbon atom they are commonly attached to form a spiro    cyclopropyl ring;-   R⁴ is CH₂; and-   R⁵ is a pyridyl, indolyl, azaindolyl, benzofuranyl, furanopyridinyl,    thienopyridinyl, benzoxazolyl, benzimidazolyl, quinolinyl, or    isoquinolinyl group, each optionally independently substituted with    one to three substituent groups,    -   wherein each substituent group of R⁵ is independently methyl,        phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,        dimethylaminocarbonyl, morpholinylcarbonyl, fluoro, chloro,        bromo, cyano, or trifluoromethyl,        or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compounds of Formula (IA),wherein:

-   R¹ is phenyl, dihydrobenzofuranyl, or benzofuranyl, each optionally    independently substituted with one to three substituent groups,    -   wherein each substituent group of R¹ is independently C₁-C₃        alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃        alkenyloxy, C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃        alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl,        nitro, or C₁-C₃ alkylthio wherein the sulfur atom is optionally        oxidized to a sulfoxide or sulfone; and-   R² and R³ are each independently hydrogen or C₁-C₃ alkyl,    or a tautomer, prodrug, solvate, or salt thereof.

In yet other aspects of the invention, one to three substituent groupsof R¹ in the compounds of Formula (IA) is independently C₁-C₃ alkylaminoor C₁-C₃ dialkylamino.

The following are representative compounds of Formula (IA) according tothe invention:

Compound Name Compound Structure 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4,6-dimethylpyridin-2- ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-2-(pyridin-2-ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(6-methylpyridin-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(4-methylpyridin-2-ylmethyl)pentan-2-ol

4-Fluoro-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-pyridin-2-ylmethylbutyl)phenol

2-(4,5-Dimethylthiazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

2-(4,5-Dimethyloxazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(3-methylpyridin-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(5-methylpyridin-2-ylmethyl)pentan-2-ol

2-Benzothiazol-2-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan- 2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(5-phenylbenzoxazol-2-ylmethyl)pentan-2-ol

2-Benzofuran-2-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan- 2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(3-methylbenzofuran-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-thiophen-2-ylmethylpentan-2-ol

5-(5-Fluoro-2-methoxyphenyl)-5-methyl-2-pyridin-2-yl-3-trifluoromethylhexan-3-ol

5-(5-Fluoro-2-methoxyphenyl)-5-methyl-2-pyridin-2-yl-3-trifluoromethylhexan-3-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(5-methylbenzooxazol-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(5-methylbenzothiazol-2-ylmethyl)pentan-2-ol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(5-methylbenzooxazol-2- ylmethyl)butyl]phenol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(5-methylbenzothiazol-2- ylmethyl)butyl]phenol

1,1,1-Trifluoro-4-methyl-4-phenyl-2-pyridin- 2-ylmethylpentan-2-ol

2-(4,6-Dimethylpyridin-2-ylmethyl)-1,1,1-trifluoro-4-methyl-4-phenylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-pyrimidin-4-ylmethylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(4-methylquinolin-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(1-phenyl-1H-pyrazol-3-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(1-methyl-1H-imidazol-2-ylmethyl)pentan-2-ol

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3- phenylisoxazole-4-carboxylicmethylamide

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-pyrazin-2-ylmethylpentan-2-ol

4-(2-Allyloxy-5-fluorophenyl)-1,1,1- trifluoro-4-methyl-2-pyridin-2-ylmethylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(3-methyl-1H-indol-2-ylmethyl)pentan-2-ol

2-Benzooxazol-2-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan- 2-ol

1,1,1 -Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2 -pyridazin-3-ylmethylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-pyridin-3-ylmethylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(5-methylpyridin-3-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(1-methyl-1H-indol-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-quinolin-2-ylmethylpentan-2-ol

4-(4-Chlorophenyl)-1,1,1-trifluoro-4-methyl-2-pyridin-2-ylmethylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-2-(6-fluoropyridin-2-ylmethyl)-4-methylpentan-2-ol

6-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy- 4-methyl-2-trifluoromethylpentyl]nicotinonitrile

2-(1H-Indol-2-ylmethyl)-1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-ol

2-(6-Chloro-4-trifluoromethylpyridin-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

2-(5-Chloro-7-fluoro-1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)- 4-methylpentan-2-ol

4-(3,4-Dichlorophenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

2-(2,6-Dichloropyridin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-isoquinolin-1-ylmethyl-4- methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

2-[3-(2,6-Dichloropyridin-4-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4- fluorophenol

4-Fluoro-2-(4,4,4-trifluoro-3-hydroxy-3- isoquinolin-1-ylmethyl-1,1-dimethylbutyl)phenol

4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-pyridin-2-ylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(6-methyl-1H-indol-2-ylmethyl)pentan-2-ol

2-(1H-Benzimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-2-(6-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-4-(3-fluorophenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(quinolin-4-ylmethyl)pentan-2-ol

4-(2,3-dihydro-5-cyanobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(2-chloropyridin-4-ylmethyl)pentan-2-ol

4-(3,4-Difluorophenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(2-chloropyridin- 4-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(2-chloropyridin-5-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(2-chloroquinolin-4-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxypyridin-4- ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- hydroxyphenyl)-4-methyl-2-(2-chloroquinolin-4-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(4-methoxyphenyl)-4-methylpentan-2-ol

4-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol

1,1,1-Trifluoro-2-(5-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-2-(5-methyl-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4- methylpentan-2-ol

2-Benzimidazol-1-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan- 2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxypyridin-2- ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(4-fluoro-2-methylphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(6-chlorobenzimidazol-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-fluoropyridin- 4-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(2-bromopyridin-4-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(7-methyl-1H-indol-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-methyl-4-quinolin-4-yl-2-quinolin-4-ylmethylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan- 2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(7-trifluoromethyl-1H-indol-2-ylmethyl)pentan- 2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(7-methyl-1H-benzoimidazol-2-ylniethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(6-trifluoromethyl-1H-indol-2-ylmethyl)pentan- 2-ol

1,1,1-Trifluoro-2-quinolin-4-ylmethyl-3-[1- (2-trifluoromethoxyphenyl)cyclopropyl]propan- 2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(6-trifluoromethyl-1H-benzoimidazol-2- ylmethyl)pentan-2-ol

2-(5-Chloro-6-fluoro-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-3-[1-(5-fluoro-2-methoxyphenyl)cyclopropyl]-2-(1H-indol-2- ylmethyl)propan-2-ol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-methyl-1H-indol-2- ylmethyl)butyl]phenol

4-Fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-1H-indol-2-ylmethyl)-3-hydroxy-1,1- dimethylbutyl]phenol

1,1,1-Trifluoro-2-(6-fluoro-1H- benzoimidazol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1- trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4- ylmethylpentan-2-ol

4-(3-Ethyl-2-methoxyphenyl)-1,1,1-trifluoro4-methyl-2-quinolin-4-ylmethylpentan-2-ol

3-[1-(2,5-Difluorophenyl)cyclopropyl]-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)propan-2-ol

1,1,1-Trifluoro-3-[1-(4- fluorophenyl)cyclopropyl]-2-(1H-indol-2-ylmethyl)propan-2-ol

2-Ethyl-6-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-2-(6-fluoro-4-methyl-1H-indol-2-ylmethyl)-4-methylpentan-2-ol

2-(4,6-Dimethyl-1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

4-(3-Ethyl-2-methoxyphenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

2-Ethyl-6-[4,4,4-trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol

2-[3-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1- dimethylbutyl]-4-fluorophenol

2-(7-Chloro-5-trifluoromethyl-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan- 2-ol

2-(5,7-Dimethyl-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methylphenyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2- ylmethyl)-4-(4-fluorophenyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2- ylmethyl)-4-(3-fluorophenyl)-4-methylpentan-2-ol

2-[3-(5,7-Dimethyl-1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1- dimethylbutyl]-4-fluorophenol

1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(3-methoxyphenyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(4-methyl-1H-indol-2- ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-(3-trifluoromethylphenyl)pentan- 2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2- ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2- ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2- ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(7-methyl-1H-benzoimidazol-2- ylmethyl)pentan-2-ol

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3H- benzoimidazole-5-carbonitrile

1,1,1-Trifluoro-4-(4-fluoro-2- methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(3-trifluoromethylphenyl)pentan-2- ol

1,1,1-Trifluoro-4-(4-fluoro-2- methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

5-Fluoro-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(5-trifluoromethyl-1H-indol-2- ylmethyl)butyl]phenol

4-(5-Bromo-4-fluoro-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4- ylmethylpentan-2-ol

2-(6-Chloro-4-methyl-1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)- 4-methylpentan-2-ol

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl- 1H-indole-6-carbonitrile

2-(2-Phenyl-4-methylimidazol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)- 4-methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2,3- dihydrobenzofuran-7-yl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

2-(2-Phenylimidazol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2,3- dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)-2-quinolin-4- ylmethylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4- methyl-4-phenylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran- 7-yl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-2-(7-fluoro-4-methyl-1H-indol-2-ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4- methyl-4-m-tolylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-naphthalen-2-ylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4- methyl-4-o-tolylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4- methyl-4-p-tolylpentan-2-ol

4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1- trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

4-(7-Bromo-2,3-dihydrobenzofuran-5-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4- ylmethylpentan-2-ol

4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-4-(1-methoxynaphthalen-2-yl)-4-methyl-2-quinolin-4-ylmethylpentan-2- ol

2-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)naphthalen-1-ol

1,1,1-Trifluoro-4-methyl-4-naphthalen-2-yl-2-quinolin-4-ylmethylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 5-carbonitrile

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 7-carbonitrile

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(1-methoxynaphthalen-2-yl)-4-methylpentan-2- ol

2-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]naphthalen-1-ol

1,1,1-Trifluoro-4-methyl-2-quinolin-4- ylmethyl-4-p-tolylpentan-2-ol

4-Chroman-8-yl-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

1,1,1-Trifluoro-4-methyl-4-phenyl-2- quinolin-4-ylmethylpentan-2-ol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2- ylmethyl)butyl]phenol

4-(6-Bromochroman-8-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2- ylmethyl)butyl]phenol

1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)pentan-2-ol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-b]pyridin-2- ylmethyl)butyl]phenol

1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-b]pyridin-2-ylmethyl)pentan-2-ol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-b]pyridin-2- ylmethyl)butyl]phenol

1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2- ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2- ylmethyl)pentan-2-ol

4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[2,3- c]pyridin-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-methyl-4-phenyl-2- quinolin-4-ylmethylpentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-2-(7-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol

1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(7-fluoroquinolin-4-ylmethyl)-4-methylpentan- 2-ol

1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(5-fluoroquinolin-4-ylmethyl)-4-methylpentan- 2-ol

1,1,1-Trifluoro-2-(7-fluoro-4-methylquinolin-8-yl)-4-(4-fluorophenyl)-4-methylpentan-2-ol

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 3-carbonitrile

2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]- 1H-indole-3-carbonitrile

2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl- 1H-indole-6-carbonitrile

1,1,1-Trifluoro-4-(2-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(2-methoxyphenyl)-4-methylpentan-2-ol

2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)- 2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3- carbonitrile

4-(5-Bromo-2-methoxyphenyl)-1,1,1- trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

4-(5-Bromo-2-methoxyphenyl)-1,1,1- trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

2-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol

1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol

2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)- 2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3- carbonitrile

4-Bromo-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol

2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 3-carbonitrile

2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-4-methyl-1H-indole-6- carbonitrile

2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6- carbonitrile

2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6- carbonitrile

2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile

1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2- ylmethyl)pentan-2-ol

4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[3,2- c]pyridin-2-ylmethyl)pentan-2-ol

2-(2-Hydroxy-4-methyl-4-phenyl-2- trifluoromethylpentyl)-1H-indole-5-carbonitrile

2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-1H-indole-3-carbonitrile

2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3- carbonitrile

1,1,1-Trifluoro-4-(4-fluoro-2- methoxyphenyl)-4-methyl-2-(5,6,7,8-tetrahydroquinolin-4-ylmethyl)pentan-2-ol

1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 3-carbonitrile

1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol

2-(2-Hydroxy-4-methyt-4-phenyl-2- trifluoromethylpentyl)-1H-indole-3-carbonitrile

5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2- ylmethyl)butyl]phenol

2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 5-carbonitrile

2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]- 1H-indole-5-carbonitrile

2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5- carbonitrile

2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5- carbonitrile

2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5- carbonitrile

4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)4- methylpentan-2-ol

1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(4-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol

1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methyl-4-phenylpentan-2-ol

2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 5-carboxylic acid methylester

1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]- 1H-indole-3-carbonitrile

1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2- ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(4-fluoro-2- methoxyphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan- 2-ol

4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(5-trifluoromethyl-1H- indol-2-ylmethyl)pentan-2-ol

1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2- ylmethyl)pentan-2-ol

2-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-indole-5- carbonitrile

5-Fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-1H-indol-2-ylmethyl)-3-hydroxy-1,1- dimethylbutyl]phenol

2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl- 1H-indole-6-carbonitrile

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-1H-pyrrolo[2,3- c]pyridin-2-ylmethyl)butyl]phenol

1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-thiophen-3-ylpentan-2-ol

1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-thiophen-3-ylpentan-2-ol

5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2- ylmethyl)butyl]phenol

1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2- ylmethyl)pentan-2-ol

2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl- 1H-indole-6-carbonitrile

3-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(4-trifluoromethyl-1H-indol-2-ylmethyl)pentan- 2-ol

4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-(5-trifluoromethyl-1H- indol-2-ylmethyl)pentan-2-ol

2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 5-carbonitrile

2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 5-carboxylic acid methylester

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 5-carboxylic acid methylester

4-(2,6-Dimethylphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol

3-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol

1,1,1-Trifluoro-4-(5-fluoro-2,3- dihydrobenzofuran-7-yl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol

1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 3-carboxylic acid methylester

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]-[2- trifluoromethylpyridin]-2-ylmethyl)butyl]phenol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]-[3- methylpyridin]-2-ylmethyl)butyl]phenol

4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]-[2- fluoropyridin]-2-ylmethyl)butyl]phenol

2-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-4-methyl- 1H-indole-6-carbonitrile

2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl- 1H-indole-6-carbonitrile

2-[4-(4-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 5-carbonitrile

1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(5-nitro-1H-indol-2-ylmethyl)pentan-2-ol

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 5-carboxylic acid amide

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 5-carboxylic aciddimethylamide

{2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indol-5-yl}morpholin-4-ylmethanone

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 6-carboxylic acid methylester

2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 6-carboxylic acid methylester

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole 6-carboxylic acid

2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole- 6-carboxylic acid

or a tautomer, prodrug, solvate, or salt thereof.

Preferred compounds of Formula (IA) include the following:

-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(pyridin-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-phenylbenzoxazol-2-ylmethyl)pentan-2-ol;-   2-Benzofuran-2-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methylbenzofuran-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   6-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trfluoromethylpentyl]nicotinonitrile;-   2-(1H-Indol-2-ylmethyl)-1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-ol;-   2-(6-Chloro-4-trifluoromethylpyridin-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   2-(5-Chloro-7-fluoro-1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   4-(3,4-Dichlorophenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(2,6-Dichloropyridin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-[3-(2,6-Dichloropyridin-4-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-di    methylbutyl]-4-fluorophenol;-   4-Fluoro-2-(4,4,4-trifluoro-3-hydroxy-3-isoquinolin-1-ylmethyl-1,1-dimethylbutyl)phenol;-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-pyridin-2-ylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   2-(1H-Benzimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(6-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(quinolin-4-ylmethyl)pentan-2-ol;-   4-(2,3-dihydro-5-cyanobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-chloropyridin-4-ylmethyl)pentan-2-ol;-   4-(3,4-Difluorophenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(2-chloropyridin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-chloroquinolin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(2-chloroquinolin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(4-methoxyphenyl)-4-methylpentan-2-ol;-   4-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol;-   1,1,1-Trifluoro-2-(5-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(5-methyl-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-Benzimidazol-1-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methylphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-chlorobenzimidazol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-fluoropyridin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-bromopyridin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-methyl-1H-benzoimidazol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-trifluoromethyl-1H-benzoimidazol-2-ylmethyl)pentan-2-ol;-   2-(5-Chloro-6-fluoro-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-3-[1-(5-fluoro-2-methoxyphenyl)cyclopropyl]-2-(1H-indol-2-ylmethyl)propan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-methyl-1H-indol-2-ylmethyl)butyl]phenol;-   4-Fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-1H-indol-2-ylmethyl)-3-hydroxy-1,1-dimethylbutyl]phenol;-   1,1,1-Trifluoro-2-(6-fluoro-1H-benzoimidazol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-yl    methylpentan-2-ol;-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(3-Ethyl-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-3-[1-(4-fluorophenyl)cyclopropyl]-2-(1H-indol-2-ylmethyl)propan-2-ol;-   2-Ethyl-6-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(6-fluoro-4-methyl-1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(4,6-Dimethyl-1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   4-(3-Ethyl-2-methoxyphenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-Ethyl-6-[4,4,4-trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol;-   2-[3-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4-fluorophenol;-   2-(7-Chloro-5-trifluoromethyl-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   2-(5,7-Dimethyl-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(4-fluorophenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(3-fluorophenyl)-4-methylpentan-2-ol;-   2-[3-(5,7-Dimethyl-1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4-fluorophenol;-   1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(3-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-(3-trifluoromethylphenyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(7-methyl-1H-benzoimidazol-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3H-benzoimidazole-5-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(3-trifluoromethylphenyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   5-Fluoro-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(5-trifluoromethyl-1H-indol-2-ylmethyl)butyl]phenol;-   4-(5-Bromo-4-fluoro-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-(6-Chloro-4-methyl-1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-(2-Phenyl-4-methylimidazol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-(2-Phenylimidazol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-phenylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-methyl-1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-m-tolylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-naphthalen-2-ylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-o-tolylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-p-tolylpentan-2-ol;-   4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(7-Bromo-2,3-dihydrobenzofuran-5-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(1-methoxynaphthalen-2-yl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)naphthalen-1-ol;-   1,1,1-Trifluoro-4-methyl-4-naphthalen-2-yl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-7-carbonitrile;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(1-methoxynaphthalen-2-yl)-4-methylpentan-2-ol;-   2-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]naphthalen-1-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-p-tolylpentan-2-ol;-   4-Chroman-8-yl-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   4-(6-Bromochroman-8-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)pentan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-b]pyridin-2-ylmethyl)pentan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-b]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(7-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(5-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   1,1,1-Trifluoro-4-(2-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(2-methoxyphenyl)-4-methylpentan-2-ol;-   2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   4-Bromo-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-1H-indole-5-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(5,6,7,8-tetrahydroquinolin-4-ylmethyl)pentan-2-ol;-   1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-1H-indole-3-carbonitrile;-   5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methyl-4-phenylpentan-2-ol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid methyl ester;-   1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   2-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   5-Fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-1H-indol-2-ylmethyl)-3-hydroxy-1,1-dimethylbutyl]phenol;-   2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-thiophen-3-ylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-thiophen-3-ylpentan-2-ol;-   5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   3-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid methyl ester;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid methyl ester;-   4-(2,6-Dimethylphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   3-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;    and-   1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carboxylic    acid methyl ester,    or a tautomer, prodrug, solvate, or salt thereof.

More preferred compounds of Formula (IA) include the following:

-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(2,6-Dichloropyridin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-[3-(2,6-Dichloropyridin-4-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4-fluorophenol;-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(1H-Benzimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(quinolin-4-ylmethyl)pentan-2-ol;-   4-(2,3-dihydro-5-cyanobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-chloropyridin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(2-chloropyridin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-chloroquinolin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(2-chloroquinolin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(4-methoxyphenyl)-4-methylpentan-2-ol;-   4-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol;-   1,1,1-Trifluoro-2-(5-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-bromopyridin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-methyl-1H-benzoimidazol-2-ylmethyl)pentan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-methyl-1H-indol-2-ylmethyl)butyl]phenol;-   4-Fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-1H-indol-2-ylmethyl)-3-hydroxy-1,1-dimethylbutyl]phenol;-   1,1,1-Trifluoro-2-(6-fluoro-1H-benzoimidazol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(3-Ethyl-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-Ethyl-6-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   2-Ethyl-6-[4,4,4-trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol;-   2-(5,7-Dimethyl-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   2-[3-(5,7-Dimethyl-1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4-fluorophenol;-   1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(3-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-(3-trifluoromethylphenyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(7-methyl-1H-benzoimidazol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(3-trifluoromethylphenyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   5-Fluoro-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   4-(5-Bromo-4-fluoro-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-(2-Phenyl-4-methylimidazol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-(2-Phenylimidazol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-phenylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-m-tolylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-naphthalen-2-ylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-o-tolylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-p-tolylpentan-2-ol;-   4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(7-Bromo-2,3-dihydrobenzofuran-5-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(1-methoxynaphthalen-2-yl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)naphthalen-1-ol;-   1,1,1-Trifluoro-4-methyl-4-naphthalen-2-yl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(1-methoxynaphthalen-2-yl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-p-tolylpentan-2-ol;-   4-Chroman-8-yl-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(6-Bromochroman-8-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-b]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(7-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(5-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   1,1,1-Trifluoro-4-(2-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(2-methoxyphenyl)-4-methylpentan-2-ol;-   2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(4,4,4-Tri    fluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   4-Bromo-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-1H-indole-5-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(5,6,7,8-tetrahydroquinolin-4-ylmethyl)pentan-2-ol;-   1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-1H-indole-3-carbonitrile;-   5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methyl-4-phenylpentan-2-ol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid methyl ester;-   1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   2-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   5-Fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-1H-indol-2-ylmethyl)-3-hydroxy-1,1-dimethylbutyl]phenol;-   2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-thiophen-3-ylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-thiophen-3-ylpentan-2-ol;-   5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   3-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid methyl ester;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid methyl ester;-   4-(2,6-Dimethylphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   3-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(4-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-nitro-1H-indol-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid amide;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid dimethylamide;-   {2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indol-5-yl}morpholin-4-ylmethanone;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-6-carboxylic    acid methyl ester;-   2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-6-carboxylic    acid methyl ester;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-6-carboxylic    acid; and-   2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-6-carboxylic    acid,    or a tautomer, prodrug, solvate, or salt thereof.

The invention also provides a method of making a compound of Formula(IA)

where R¹, R², R³, R⁴, and R⁵ are as defined above, the methodcomprising:

-   (a) reacting an ester of Formula (II) with a suitable reducing agent    in a suitable solvent to form a diol of Formula (III)

-   (b) reacting the diol of Formula (III) under suitable oxidative    cleavage conditions to form a ketone of Formula (IV)

-   (c) reacting the ketone of Formula (IV) with a suitable    organometallic reagent R⁵R⁴M where M is Li or MgX and X is Cl, Br,    or I, in a suitable solvent to form the compound of Formula (IA)

-   (a′) reacting the trifluoroacetamide of Formula (X) with a vinyl    magnesium bromide bearing R² and R³ in a suitable solvent to provide    the trifluoromethylenone of Formula (XI)

-   (b′) reacting the trifluoromethylenone of Formula (XI) with a    suitable organocopper reagent generated from an organometallic    reagent R⁵R⁴M where M is Li or MgX and a copper salt CuX, where X is    Cl, Br, or I, in a suitable solvent to form the ketone of Formula    (IV)

and performing step (c) as set forth above.

The instant invention is also directed to compounds of Formula (IB)

wherein:

-   R¹ is an aryl or heteroaryl group, each optionally independently    substituted with one to three substituent groups,    -   wherein each substituent group of R¹ is independently C₁-C₅        alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl,        heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy,        C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅        alkanoyloxy, C₁-C₅ alkanoyl, aroyl, aminocarbonyl, C₁-C₅        alkylaminocarbonyl, C₁-C₅ dialkylaminocarbonyl,        aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅        dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅        alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl,        C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen,        hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy,        nitro, or amino wherein the nitrogen atom is optionally        independently mono- or di-substituted by C₁-C₅ alkyl or aryl; or        ureido wherein either nitrogen atom is optionally independently        substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the        sulfur atom is optionally oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R¹ is optionally            independently substituted with one to three substituent            groups selected from methyl, methoxy, halogen, hydroxy, oxo,            cyano, or amino,-   R² and R³ are each independently C₁-C₅ alkyl;-   R⁴ is C₁-C₅ alkyl, C₂-C₅ alkenyl, or C₂-C₅ alkynyl, each optionally    independently substituted with one to three substituent groups,    -   wherein each substituent group of R⁴ is independently C₁-C₃        alkyl, hydroxy, halogen, or oxo;-   R⁵ is a heteroaryl group optionally independently substituted with    one to three substituent groups,    -   wherein each substituent group of R⁵ is independently C₁-C₅        alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl,        heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy,        C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅        alkanoyloxy, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅        alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅        alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅        alkylsulfonylamino, C₁-C₅ alkylaminosulfonyl, C₁-C₅        dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano,        trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro,        or amino wherein the nitrogen atom is optionally independently        mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either        nitrogen atom is optionally independently substituted with C₁-C₅        alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally        oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R⁵ is optionally            independently substituted with one to three substituent            groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen,            hydroxy, oxo, cyano, amino, or trifluoromethyl; and-   R⁶ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, carbocycle,    heterocyclyl, aryl, heteroaryl, carbocycle-C₁-C₈ alkyl, aryl-C₁-C₈    alkyl, aryl-C₁-C₈ haloalkyl, heterocyclyl-C₁-C₈ alkyl,    heteroaryl-C₁-C₈ alkyl, carbocycle-C₂-C₈ alkenyl, aryl-C₂-C₈    alkenyl, heterocyclyl-C₂-C₈ alkenyl, or heteroaryl-C₂-C₈ alkenyl,    each optionally independently substituted with one to three    substituent groups,    -   wherein each substituent group of R⁶ is independently C₁-C₅        alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, phenyl,        C₁-C₅ alkoxy, phenoxy, C₁-C₅ alkanoyl, aroyl, C₁-C₅        alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyloxy, C₁-C₅        alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy,        aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅        dialkylaminocarbonyl, C₁-C₅ alkanoylamino, C₁-C₅        alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, C₁-C₅        alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen,        hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino        wherein the nitrogen atom is optionally independently mono- or        di-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen        atom is optionally independently substituted with C₁-C₅ alkyl;        or C₁-C₅ alkylthio wherein the sulfur atom is optionally        oxidized to a sulfoxide or sulfone,-   wherein R⁶ cannot be trifluoromethyl,    or a tautomer, prodrug, solvate, or salt thereof.

Another aspect of the invention includes compounds of Formula (IB),wherein:

-   R¹ is thienyl, phenyl, naphthyl, dihydrobenzofuranyl, benzofuranyl,    chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl,    benzothienyl, benzodioxolanyl, benzoxazolyl, benzisoxazolyl,    benzpyrazolyl, benzimidazolyl, quinolinyl, pyridinyl, pyrimidinyl,    or pyrazinyl, each optionally independently substituted with one to    three substituent groups,    -   wherein each substituent group of R¹ is independently C₁-C₃        alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃        alkenyloxy, C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃        alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl,        nitro, or C₁-C₃ alkylthio wherein the sulfur atom is optionally        oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R¹ is optionally            independently substituted with a substituent group selected            from methyl, methoxy, halogen, hydroxy, oxo, cyano, or            amino;-   R² and R³ are each independently C₁-C₃ alkyl;-   R⁴ is CH₂;-   R⁵ is an imidazolyl, pyridyl, indolyl, azaindolyl, diazaindolyl,    benzofuranyl, furanopyridinyl, furanopyrimidinyl, benzothienyl,    thienopyridinyl, thienopyrimidinyl, benzoxazolyl, oxazolopyridinyl,    benzothiazolyl, thiazolopyridinyl, benzimidazolyl,    imidazolopyridinyl, quinolinyl, or isoquinolinyl group, each    optionally independently substituted with one to three substituent    groups,    -   wherein each substituent group of R⁵ is independently C₁-C₃        alkyl, C₂-C₃ alkenyl, phenyl, C₁-C₃ alkoxy, methoxycarbonyl,        aminocarbonyl, C₁-C₃ alkylaminocarbonyl, C₁-C₃        dialkylaminocarbonyl, heterocyclylcarbonyl, fluoro, chloro,        bromo, cyano, trifluoromethyl, or C₁-C₃ alkylthio wherein the        sulfur atom is optionally oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R⁵ is optionally            independently substituted with a substituent group selected            from methyl, methoxy, fluoro, chloro, bromo, or            trifluoromethyl; and-   R⁶ is C₁-C₅ alkyl, C₂-C₅ alkenyl, C₃-C₆ cycloalkyl, phenyl, C₃-C₆    cycloalkyl-C₁-C₃ alkyl, phenyl-C₁-C₃ alkyl, phenyl-C₁-C₃ haloalkyl,    C₃-C₆ cycloalkyl-C₂-C₃ alkenyl, phenyl-C₂-C₃ alkenyl, each    optionally independently substituted with one to three substituent    groups,    -   wherein each substituent group of R⁶ is independently C₁-C₃        alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy,        aminocarbonyl, C₁-C₃ alkylaminocarbonyl, C₁-C₃        dialkylaminocarbonyl, halogen, hydroxy, carboxy, cyano,        trifluoromethyl, nitro, or C₁-C₃ alkylthio wherein the sulfur        atom is optionally oxidized to a sulfoxide or sulfone,        or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compounds of Formula (IB),wherein:

-   R¹ is thienyl, phenyl, naphthyl, pyridyl, chromanyl,    dihydrobenzofuranyl, or benzofuranyl, each optionally independently    substituted with one or two substituent groups,    -   wherein each substituent group of R¹ is independently methyl,        ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy,        trifluoromethyl, or cyano;-   R² and R³ are each methyl;-   R⁴ is CH₂;-   R⁵ is a pyridyl, indolyl, azaindolyl, benzofuranyl, furanopyridinyl,    thienopyridinyl, benzoxazolyl, benzimidazolyl, quinolinyl, or    isoquinolinyl group, each optionally independently substituted with    one to three substituent groups,    -   wherein each substituent group of R⁵ is independently methyl,        phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,        dimethylaminoaminocarbonyl, morpholinylcarbonyl, fluoro, chloro,        bromo, cyano, or trifluoromethyl; and-   R⁶ is C₁-C₅ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl-methyl-, or    benzyl, each optionally independently substituted with one to three    substituent groups,    -   wherein each substituent group of R⁶ is independently methyl,        methoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or        hydroxy,        or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compounds of Formula (IB),wherein:

-   R¹ is phenyl, dihydrobenzofuranyl, or benzofuranyl, each optionally    independently substituted with one to three substituent groups,    -   wherein each substituent group of R¹ is independently C₁-C₃        alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃        alkenyloxy, C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃        alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl,        nitro, or C₁-C₃ alkylthio wherein the sulfur atom is optionally        oxidized to a sulfoxide or sulfone; and-   R² and R³ are each independently C₁-C₃ alkyl,    or a tautomer, prodrug, solvate, or salt thereof.

In yet other aspects of the invention, one to three substituent groupsof R¹ in the compounds of Formula (IB) is independently C₁-C₃ alkylaminoor C₁-C₃ dialkylamino.

The following are representative compounds of Formula (IB) according tothe invention:

Compound Name Compound Structure 2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-1-(1H-indol-2-yl)-4- methylpentan-2-ol

5-(5-Fluoro-2-methoxyphenyl)-3-(1H-indol-2-ylmethyl)-2,5-dimethylhexan-3-ol

5-(5-Fluoro-2-methoxyphenyl)-3-(1H-indol- 2-ylmethyl)-5-methylhexan-3-ol

2-Cyclohexylmethyl-1-(4,6- dimethylpyridin-2-yl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

2-Cyclohexylmethyl-4-(5-fluoro-2- methoxyphenyl)-1-(1H-indol-2-yl)-4-methylpentan-2-ol

7-(5-Fluoro-2-methoxyphenyl)-5-(1H-indol- 2-ylmethyl)-7-methyloctan-5-ol

2-(Benzimidazol-2-ylmethyl)-4-methyl-4- (pyrrol-1-yl)pentan-2-ol

1-(1H-Benzoimidazol-2-yl)-2- cyclohexylmethyl-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

5-(5-Fluoro-2-methoxyphenyl)-3- (benzimidazol-2-ylmethyl)-2,2,5-trimethylhexan-3-ol

4-(5-Fluoro-2-methoxyphenyl)-2- fluoromethyl-1-(1H-indol-2-yl)-4-methylpentan-2-ol

2-Cyclopropyl-4-(2,3-dihydrobenzofuran-7-yl)-1-(1H-indol-2-yl)-4-methylpentan-2-ol

2-Cyclopropyl-4-(2,3-dihydrobenzofuran-7-yl)-1-(quinolin-4-yl)-4-methylpentan-2-ol

2-Cyclopropyl-4-(5-fluoro-2- methoxyphenyl)-1-(6-cyano-4-methylindol-2-yl)-4-methylpentan-2-ol

2-Cyclopropyl-4-(5-fluoro-2- methoxyphenyl)-4-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)pentan-2-ol

4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-cyclopropyl-4-methyl-1-(1H-pyrrolo[2,3- c]pyridin-2-yl)pentan-2-ol

or a tautomer, prodrug, solvate, or salt thereof.

Preferred compounds of Formula (IB) include the following:

-   2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-1-(1H-indol-2-yl)-4-methylpentan-2-ol;-   5-(5-Fluoro-2-methoxyphenyl)-3-(indol-2-ylmethyl)-2,5-dimethylhexan-3-ol;-   5-(5-Fluoro-2-methoxyphenyl)-3-(indol-2-ylmethyl)-5-methylhexan-3-ol;-   1-Cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-2-(indol-2-ylmethyl)-4-methylpentan-2-ol;-   5-(5-Fluoro-2-methoxyphenyl)-3-(benzimidazol-2-ylmethyl)-2,2,5-trimethylhexan-3-ol;-   4-(5-Fluoro-2-methoxyphenyl)-2-fluoromethyl-1-(1H-indol-2-yl)-4-methylpentan-2-ol;-   2-Cyclopropyl-4-(2,3-dihydrobenzofuran-7-yl)-1-(1H-indol-2-yl)-4-methylpentan-2-ol;-   2-Cyclopropyl-4-(2,3-dihydrobenzofuran-7-yl)-1-(quinolin-4-yl)-4-methylpentan-2-ol;-   2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-1-(6-cyano-4-methylindol-2-yl)-4-methylpentan-2-ol;-   2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)pentan-2-ol;    and-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-cyclopropyl-4-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)pentan-2-ol,    or a tautomer, prodrug, solvate, or salt thereof.

More preferred compounds of Formula (IB) include:

-   2-Cyclopropyl-4-(2,3-dihydrobenzofuran-7-yl)-1-(1H-indol-2-yl)-4-methylpentan-2-ol;    and-   2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)pentan-2-ol;    or a tautomer, prodrug, solvate, or salt thereof.

The invention further provides methods of making a compound of Formula(IB). One method of making a compound of Formula (IB)

where R¹ is an optionally substituted 2-methoxyphenyl group and R², R³,R⁴, R⁵, and R⁶ are as defined above, the method comprising:

-   -   (a) reacting an optionally substituted phenol of Formula (XXII)        with an acryloyl chloride of Formula (XIII) in the presence of a        suitable base, followed by cyclization of the intermediate ester        by treatment with a suitable Lewis acid to form a lactone of        Formula (XIV)

-   -   (b) reacting the lactone of Formula (XIV) with a suitable amine        HNR′R″, followed by treatment of the intermediate phenol with        methyl iodide in the presence of a suitable base to form an        amide of Formula (XV)

-   -   (c) reacting the amide of Formula (XV) with a suitable        organometallic reagent R⁶M, where M is Li or MgX and X is Cl,        Br, or I, in a suitable solvent to form a ketone of Formula        (XVI)

-   -   (d) reacting the ketone of Formula (XVI) with a suitable        organometallic reagent R⁵R⁴M where M is Li or MgX and X is Cl,        Br, or I, in a suitable solvent to form the compound of Formula        (IB)

A second method for making a compound of Formula (IB) comprises:

-   -   (a′) reacting an amide of Formula (XVII) with a vinyl magnesium        bromide bearing R² and R³ of Formula (XVIII) in a suitable        solvent to provide an enone of Formula (XIX)

-   -   (b′) reacting the enone of Formula (XIX) with a suitable        organocopper reagent generated from an organometallic reagent        R¹M, where M is Li or MgX, and a copper salt CuX, where X is Cl,        Br, or I, in a suitable solvent to form a ketone of Formula (XX)

-   -   (c′) reacting the ketone of Formula (XX) with a suitable        organometallic reagent R⁵R⁴M, where M is Li or MgX, and X is Cl,        Br, or I, in a suitable solvent to form the compound of Formula        (IB)

In another aspect of the invention, the compounds according to theinvention are formulated into pharmaceutical compositions comprising aneffective amount, preferably a pharmaceutically effective amount, of acompound according to the invention or a tautomer, prodrug, solvate, orsalt thereof, and a pharmaceutically acceptable excipient or carrier.

The invention also provides a method of modulating the glucocorticoidreceptor function in a patient, the method comprising administering tothe patient an effective amount of a compound according to the inventionor a tautomer, prodrug, solvate, or salt thereof.

The invention further provides a method of treating a disease-state orcondition mediated by the glucocorticoid receptor function in a patientin need of such treatment, the method comprising administering to thepatient an effective amount of a pharmaceutically acceptable compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof.

In addition, the invention also provides a method of treating adisease-state or condition selected from: type II diabetes, obesity,cardiovascular diseases, hypertension, arteriosclerosis, neurologicaldiseases, adrenal and pituitary tumors, and glaucoma, in a patient inneed of such treatment, the method comprising administering to thepatient an effective amount of a pharmaceutically acceptable compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof.

The invention provides a method of treating a disease characterized byinflammatory, allergic, or proliferative processes, in a patient in needof such treatment, the method comprising administering to the patient aneffective amount of a pharmaceutically acceptable compound according tothe invention or a tautomer, prodrug, solvate, or salt thereof. In apreferred embodiment of the invention, the disease characterized byinflammatory, allergic, or proliferative processes is selected from: (i)lung diseases; (ii) rheumatic diseases or autoimmune diseases or jointdiseases; (iii) allergic diseases; (iv) vasculitis diseases; (v)dermatological diseases; (vi) renal diseases; (vii) hepatic diseases;(viii) gastrointestinal diseases; (ix) proctological diseases; (x) eyediseases; (xi) diseases of the ear, nose, and throat (ENT) area; (xii)neurological diseases; (xiii) blood diseases; (xiv) tumor diseases; (xv)endocrine diseases; (xvi) organ and tissue transplantations andgraft-versus-host diseases; (xvii) severe states of shock; (xviii)substitution therapy; and (xix) pain of inflammatory genesis. In anotherpreferred embodiment of the invention, the disease characterized byinflammatory, allergic, or proliferative processes is selected from:type I diabetes, osteoarthritis, Guillain-Barre syndrome, restenosisfollowing percutaneous transluminal coronary angioplasty, Alzheimerdisease, acute and chronic pain, atherosclerosis, reperfusion injury,bone resorption diseases, congestive heart failure, myocardialinfarction, thermal injury, multiple organ injury secondary to trauma,acute purulent meningitis, necrotizing enterocolitis, and syndromesassociated with hemodialysis, leukopheresis, and granulocytetransfusion.

The invention further provides methods of treating the disease-states orconditions mentioned above, in a patient in need of such treatment, themethods comprising sequentially or simultaneously administering to thepatient: (a) an effective amount of a pharmaceutically acceptablecompound according to the invention or a tautomer, prodrug, solvate, orsalt thereof; and (b) a pharmaceutically acceptable glucocorticoid.

The invention further provides a method of assaying the glucocorticoidreceptor function in a sample, comprising: (a) contacting the samplewith a selected amount of a compound according to the invention or atautomer, prodrug, solvate, or salt thereof; and (b) detecting theamount of the compound according to the invention or a tautomer,prodrug, solvate, or salt thereof bound to glucocorticoid receptors inthe sample. In a preferred embodiment of the invention, the compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof is labeled with a detectable marker selected from: a radiolabel,fluorescent tag, a chemiluminescent tag, a chromophore, and a spinlabel.

The invention also provides a method of imaging the glucocorticoidreceptor distribution in a sample or patient, the method comprising: (a)contacting the sample or administering to a patient a compound accordingto the invention or a tautomer, prodrug, solvate, or salt thereof havinga detectable marker; (b) detecting the spatial distribution and amountof the compound according to the invention or a tautomer, prodrug,solvate, or salt thereof having a detectable marker bound toglucocorticoid receptors in the sample or patient using an imaging meansto obtain an image; and (c) displaying an image of the spatialdistribution and amount of the compound according to the invention or atautomer, prodrug, solvate, or salt thereof having a detectable markerbound to glucocorticoid receptors in the sample. In a preferredembodiment of the invention, the imaging means is selected from:radioscintigraphy, nuclear magnetic resonance imaging (MRI), computedtomography (CT scan), or positron emission tomography (PET).

The invention also provides a kit for the in vitro diagnosticdetermination of the glucocorticoid receptor function in a sample,comprising: (a) a diagnostically effective amount of a compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof; and (b) instructions for use of the diagnostic kit.

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms and Conventions Used

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification and appendedclaims, however, unless specified to the contrary, the following termshave the meaning indicated and the following conventions are adhered to.

A. Chemical Nomenclature, Terms, and Conventions

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁-C₁₀ alkylmeans an alkyl group or radical having 1 to 10 carbon atoms. The term“lower” applied to any carbon-containing group means a group containingfrom 1 to 8 carbon atoms, as appropriate to the group (i.e., a cyclicgroup must have at least 3 atoms to constitute a ring). In general, forgroups comprising two or more subgroups, the last named group is theradical attachment point, for example, “alkylaryl” means a monovalentradical of the formula Alk-Ar—, while “arylalkyl” means a monovalentradical of the formula Ar-Alk- (where Alk is an alkyl group and Ar is anaryl group). Furthermore, the use of a term designating a monovalentradical where a divalent radical is appropriate shall be construed todesignate the respective divalent radical and vice versa. Unlessotherwise specified, conventional definitions of terms control andconventional stable atom valences are presumed and achieved in allformulas and groups.

The terms “alkyl” or “alkyl group” mean a branched or straight-chainsaturated aliphatic hydrocarbon monovalent radical. This term isexemplified by groups such as methyl, ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), and thelike. It may be abbreviated “Alk”.

The terms “alkenyl” or “alkenyl group” mean a branched or straight-chainaliphatic hydrocarbon monovalent radical containing at least onecarbon-carbon double bond. This term is exemplified by groups such asethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl,n-pentenyl, heptenyl, octenyl, decenyl, and the like.

The terms “alkynyl” or “alkynyl group” mean a branched or straight-chainaliphatic hydrocarbon monovalent radical containing at least onecarbon-carbon triple bond. This term is exemplified by groups such asethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl,heptynyl, octynyl, decynyl, and the like.

The terms “alkylene” or “alkylene group” mean a branched orstraight-chain saturated aliphatic hydrocarbon divalent radical havingthe specified number of carbon atoms. This term is exemplified by groupssuch as methylene, ethylene, propylene, n-butylene, and the like, andmay alternatively and equivalently be denoted herein as -(alkyl)-.

The terms “alkenylene” or “alkenylene group” mean a branched orstraight-chain aliphatic hydrocarbon divalent radical having thespecified number of carbon atoms and at least one carbon-carbon doublebond. This term is exemplified by groups such as ethenylene,propenylene, n-butenylene, and the like, and may alternatively andequivalently be denoted herein as -(alkylenyl)-.

The terms “alkynylene” or “alkynylene group” mean a branched orstraight-chain aliphatic hydrocarbon divalent radical containing atleast one carbon-carbon triple bond. This term is exemplified by groupssuch as ethynylene, propynylene, n-butynylene, 2-butynylene,3-methylbutynylene, n-pentynylene, heptynylene, octynylene, decynylene,and the like, and may alternatively and equivalently be denoted hereinas -(alkynyl)-.

The terms “alkoxy” or “alkoxy group” mean a monovalent radical of theformula AlkO—, where Alk is an alkyl group. This term is exemplified bygroups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy,tert-butoxy, pentoxy, and the like.

The terms “aryloxy”, “aryloxy group”, mean a monovalent radical of theformula ArO—, where Ar is aryl. This term is exemplified by groups suchas phenoxy, naphthoxy, and the like.

The terms “alkylcarbonyl”, “alkylcarbonyl group”, “alkanoyl”, or“alkanoyl group” mean a monovalent radical of the formula AlkC(O)—,where Alk is alkyl or hydrogen.

The terms “arylcarbonyl”, “arylcarbonyl group”, “aroyl” or “aroyl group”mean a monovalent radical of the formula ArC(O)—, where Ar is aryl.

The terms “acyl” or “acyl group” mean a monovalent radical of theformula RC(O)—, where R is a substituent selected from hydrogen or anorganic substituent. Exemplary substituents include alkyl, aryl,arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, andthe like. As such, the terms comprise alkylcarbonyl groups andarylcarbonyl groups.

The terms “acylamino” or “acylamino group” mean a monovalent radical ofthe formula RC(O)N(R)—, where each R is a substituent selected fromhydrogen or a substituent group.

The terms “alkoxycarbonyl” or “alkoxycarbonyl group” mean a monovalentradical of the formula AlkO—C(O)—, where Alk is alkyl. Exemplaryalkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl,tert-butyloxycarbonyl, and the like.

The terms “alkylaminocarbonyloxy” or “alkylaminocarbonyloxy group” meana monovalent radical of the formula R₂NC(O)O—, where each R isindependently hydrogen or lower alkyl.

The term “alkoxycarbonylamino” or “alkoxycarbonylamino group” mean amonovalent radical of the formula ROC(O)NH—, where R is lower alkyl.

The terms “alkylcarbonylamino” or “alkylcarbonylamino group” or“alkanoylamino” or “alkanoylamino groups” mean a monovalent radical ofthe formula AlkC(O)NH—, where Alk is alkyl. Exemplary alkylcarbonylaminogroups include acetamido (CH₃C(O)NH—).

The terms “alkylaminocarbonyloxy” or “alkylaminocarbonyloxy group” meana monovalent radical of the formula AlkNHC(O)O—, where Alk is alkyl.

The terms “amino” or “amino group” mean an —NH₂ group.

The terms “alkylamino” or “alkylamino group” mean a monovalent radicalof the formula (Alk)NH—, where Alk is alkyl. Exemplary alkylamino groupsinclude methylamino, ethylamino, propylamino, butylamino,tert-butylamino, and the like.

The terms “dialkylamino” or “dialkylamino group” mean a monovalentradical of the formula (Alk)(Alk)N—, where each Alk is independentlyalkyl. Exemplary dialkylamino groups include dimethylamino,methylethylamino, diethylamino, dipropylamino, ethylpropylamino, and thelike.

The terms “substituted amino” or “substituted amino group” mean amonovalent radical of the formula —NR₂, where each R is independently asubstituent selected from hydrogen or the specified substituents (butwhere both Rs cannot be hydrogen). Exemplary substituents include alkyl,alkanoyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heteroaryl,heteroarylalkyl, and the like.

The terms “alkoxycarbonylamino” or “alkoxycarbonylamino group” mean amonovalent radical of the formula AlkOC(O)NH—, where Alk is alkyl.

The terms “ureido” or “ureido group” mean a monovalent radical of theformula R₂NC(O)NH—, where each R is independently hydrogen or alkyl.

The terms “halogen” or “halogen group” mean a fluoro, chloro, bromo, oriodo group.

The term “halo” means one or more hydrogen atoms of the group arereplaced by halogen groups.

The terms “haloalkyl” or “haloalkyl group” mean a branched orstraight-chain saturated aliphatic hydrocarbon monovalent radical,wherein one or more hydrogen atoms thereof are each independentlyreplaced with halogen atoms. This term is exemplified by groups such aschloromethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropyl, 2-iodobutyl,1-chloro-2-bromo-3-fluoropentyl, and the like.

The terms “sulfanyl”, “sulfanyl group”, “thioether”, or “thioethergroup” mean a divalent radical of the formula —S—.

The terms “alkylthio” or “alkylthio group” mean a monovalent radical ofthe formula AlkS—, where Alk is alkyl. Exemplary groups includemethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and thelike.

The terms “sulfonyl” or “sulfonyl group” mean a divalent radical of theformula —SO₂—.

The terms “sulfonylamino” or “sulfonylamino group” mean a divalentradical of the formula —SO₂NR—, where R is a hydrogen or a substituentgroup.

The terms “aminosulfonyl” or “aminosulfonyl group” mean a monovalentradical of the formula NR₂SO₂—, where R is each independently a hydrogenor a substituent group.

The terms “carbocycle” or “carbocyclic group” mean a stable aliphatic 3-to 15-membered monocyclic or polycyclic monovalent or divalent radicalconsisting solely of carbon and hydrogen atoms which may comprise one ormore fused or bridged ring(s), preferably a 5- to 7-membered monocyclicor 7- to 10-membered bicyclic ring. Unless otherwise specified, thecarbocycle may be attached at any carbon atom which results in a stablestructure and, if substituted, may be substituted at any suitable carbonatom which results in a stable structure. The term comprises cycloalkyl(including spiro cycloalkyl), cycloalkylene, cycloalkenyl,cycloalkenylene, cycloalkynyl, and cycloalkynylene, and the like.

The terms “cycloalkyl” or “cycloalkyl group” mean a stable aliphaticsaturated 3- to 15-membered monocyclic or polycyclic monovalent radicalconsisting solely of carbon and hydrogen atoms which may comprise one ormore fused or bridged ring(s), preferably a 5- to 7-membered monocyclicor 7- to 10-membered bicyclic ring. Unless otherwise specified, thecycloalkyl ring may be attached at any carbon atom which results in astable structure and, if substituted, may be substituted at any suitablecarbon atom which results in a stable structure. Exemplary cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornanyl, adamantyl,tetrahydronaphthyl (tetralin), 1-decalinyl, bicyclo[2.2.2]octanyl,1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and thelike.

The terms “cycloalkenyl” or “cycloalkenyl group” mean a stable aliphatic3- to 15-membered monocyclic or polycyclic monovalent radical having atleast one carbon-carbon double bond and consisting solely of carbon andhydrogen atoms which may comprise one or more fused or bridged ring(s),preferably a 5- to 7-membered monocyclic or 7- to 10-membered bicyclicring. Unless otherwise specified, the cycloalkenyl ring may be attachedat any carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkenyl groups includecyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,cyclodecenyl, norbornenyl, 2-methylcyclopentenyl, 2-methylcyclooctenyl,and the like.

The terms “cycloalkynyl” or “cycloalkynyl group” mean a stable aliphatic8- to 15-membered monocyclic or polycyclic monovalent radical having atleast one carbon-carbon triple bond and consisting solely of carbon andhydrogen atoms which may comprise one or more fused or bridged ring(s),preferably a 8- to 10-membered monocyclic or 12- to 15-membered bicyclicring. Unless otherwise specified, the cycloalkynyl ring may be attachedat any carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkynyl groups include,cyclooctynyl, cyclononynyl, cyclodecynyl, 2-methylcyclooctynyl, and thelike.

The terms “cycloalkylene” or “cycloalkylene group” mean a stablesaturated aliphatic 3- to 15-membered monocyclic or polycyclic divalentradical consisting solely of carbon and hydrogen atoms which maycomprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring. Unlessotherwise specified, the cycloalkyl ring may be attached at any carbonatom which results in a stable structure and, if substituted, may besubstituted at any suitable carbon atom which results in a stablestructure. Exemplary cycloalkylene groups include cyclopentylene, andthe like.

The terms “cycloalkenylene” or “cycloalkenylene group” mean a stablealiphatic 5- to 15-membered monocyclic or polycyclic divalent radicalhaving at least one carbon-carbon double bond and consisting solely ofcarbon and hydrogen atoms which may comprise one or more fused orbridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to10-membered bicyclic ring. Unless otherwise specified, thecycloalkenylene ring may be attached at any carbon atom which results ina stable structure and, if substituted, may be substituted at anysuitable carbon atom which results in a stable structure. Exemplarycycloalkenylene groups include cyclopentenylene, cyclohexenylene,cycloheptenylene, cyclooctenylene, cyclononenylene, cyclodecenylene,norbornenylene, 2-methylcyclopentenylene, 2-methylcyclooctenylene, andthe like.

The terms “cycloalkynylene” or “cycloalkynylene group” mean a stablealiphatic 8- to 15-membered monocyclic or polycyclic divalent radicalhaving at least one carbon-carbon triple bond and consisting solely ofcarbon and hydrogen atoms which may comprise one or more fused orbridged ring(s), preferably a 8- to 10-membered monocyclic or 12- to15-membered bicyclic ring. Unless otherwise specified, thecycloalkynylene ring may be attached at any carbon atom which results ina stable structure and, if substituted, may be substituted at anysuitable carbon atom which results in a stable structure. Exemplarycycloalkynylene groups include cyclooctynylene, cyclononynylene,cyclodecynylene, 2-methylcyclooctynylene, and the like.

The terms “aryl” or “aryl group” mean an aromatic carbocyclic monovalentor divalent radical of from 6 to 14 carbon atoms having a single ring(e.g., phenyl or phenylene) or multiple condensed rings (e.g., naphthylor anthranyl). Unless otherwise specified, the aryl ring may be attachedat any suitable carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary aryl groups include phenyl,naphthyl, anthryl, phenanthryl, indanyl, indenyl, biphenyl, and thelike. It may be abbreviated “Ar”.

The terms “heteroaryl” or “heteroaryl group” mean a stable aromatic 5-to 14-membered, monocyclic or polycyclic monovalent or divalent radicalwhich may comprise one or more fused or bridged ring(s), preferably a 5-to 7-membered monocyclic or 7- to 10-membered bicyclic radical, havingfrom one to four heteroatoms in the ring(s) independently selected fromnitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms mayoptionally be oxidized and any nitrogen heteroatom may optionally beoxidized or be quaternized. Unless otherwise specified, the heteroarylring may be attached at any suitable heteroatom or carbon atom whichresults in a stable structure and, if substituted, may be substituted atany suitable heteroatom or carbon atom which results in a stablestructure. Exemplary and preferred heteroaryls include furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl,azaindolizinyl, indolyl, azaindolyl, diazaindolyl, dihydroindolyl,dihydroazaindoyl, isoindolyl, azaisoindolyl, benzofuranyl,furanopyridinyl, furanopyrimidinyl, furanopyrazinyl, furanopyridazinyl,dihydrobenzofuranyl, dihydrofuranopyridinyl, dihydrofuranopyrimidinyl,benzodioxolanyl, benzothienyl, thienopyridinyl, thienopyrimidinyl,thienopyrazinyl, thienopyridazinyl, dihydrobenzothienyl,dihydrothienopyridinyl, dihydrothienopyrimidinyl, indazolyl,azaindazolyl, diazaindazolyl, benzimidazolyl, imidazopyridinyl,benzthiazolyl, thiazolopyridinyl, thiazolopyrimidinyl, benzoxazolyl,oxazolopyridinyl, oxazolopyrimidinyl, benzisoxazolyl, purinyl,chromanyl, azachromanyl, quinolizinyl, quinolinyl, dihydroquinolinyl,tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl,tetrahydroisoquinolinyl, cinnolinyl, azacinnolinyl, phthalazinyl,azaphthalazinyl, quinazolinyl, azaquinazolinyl, quinoxalinyl,azaquinoxalinyl, naphthyridinyl, dihydronaphthyridinyl,tetrahydronaphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, and phenoxazinyl, and the like.

The terms “heterocycle”, “heterocycle group”, “heterocyclyl”, or“heterocyclyl group” mean a stable non-aromatic 5- to 14-memberedmonocyclic or polycyclic, monovalent or divalent, ring which maycomprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring, having fromone to three heteroatoms in the ring(s) independently selected fromnitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms mayoptionally be oxidized and any nitrogen heteroatom may optionally beoxidized or be quaternized. Unless otherwise specified, the heterocyclylring may be attached at any suitable heteroatom or carbon atom whichresults in a stable structure and, if substituted, may be substituted atany suitable heteroatom or carbon atom which results in a stablestructure. Exemplary and preferred heterocycles include pyrrolinyl,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, and thelike.

The term “compounds of Formula (I)” and equivalent expressions are meanto embrace either or both of compounds of Formula (IA) and compounds ofFormula (IB) as the context permits.

The term “compounds of the invention” and equivalent expressions aremeant to embrace compounds of Formula (I) as herein described, includingthe tautomers, the prodrugs, the salts, particularly thepharmaceutically acceptable salts, and the solvates and hydratesthereof, where the context so permits. In general and preferably, thecompounds of the invention and the formulas designating the compounds ofthe invention are understood to only include the stable compoundsthereof and exclude unstable compounds, even if an unstable compoundmight be considered to be literally embraced by the compound formula.Similarly, reference to intermediates, whether or not they themselvesare claimed, is meant to embrace their salts and solvates, where thecontext so permits. For the sake of clarity, particular instances whenthe context so permits are sometimes indicated in the text, but theseinstances are purely illustrative and it is not intended to excludeother instances when the context so permits.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstances may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “optionally substitutedaryl” means that the aryl radical may or may not be substituted and thatthe description includes both substituted aryl radicals and arylradicals having no substitution.

The terms “stable compound” or “stable structure” mean a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticor diagnostic agent. For example, a compound which would have a“dangling valency” or is a carbanion is not a compound contemplated bythe invention.

The term “substituted” means that any one or more hydrogens on an atomof a group or moiety, whether specifically designated or not, isreplaced with a selection from the indicated group of substituents,provided that the atom's normal valency is not exceeded and that thesubstitution results in a stable compound. If a bond to a substituent isshown to cross the bond connecting two atoms in a ring, then suchsubstituent may be bonded to any atom on the ring. When a substituent islisted without indicating the atom via which such substituent is bondedto the rest of the compound, then such substituent may be bonded via anyatom in such substituent. For example, when the substituent ispiperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise,such piperazinyl, piperidinyl, or tetrazolyl group may be bonded to therest of the compound of the invention via any atom in such piperazinyl,piperidinyl, or tetrazolyl group. Generally, when any substituent orgroup occurs more than one time in any constituent or compound, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Thus, for example, if a group is shown to besubstituted with 0 to 2 R⁵, then such group is optionally substitutedwith up to two R⁵ groups and R⁵ at each occurrence is selectedindependently from the defined list of possible R⁵. Such combinations ofsubstituents and/or variables, however, are permissible only if suchcombinations result in stable compounds.

In a specific embodiment, the term “about” or “approximately” meanswithin 20%, preferably within 10%, and more preferably within 5% of agiven value or range.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

B. Salt, Prodrug, Derivative, and Solvate Terms and Conventions

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative or carrier of the parent compound or active drug substancewhich undergoes at least some biotransformation prior to exhibiting itspharmacological effect(s). In general, such prodrugs have metabolicallycleavable groups and are rapidly transformed in vivo to yield the parentcompound, for example, by hydrolysis in blood, and generally includeesters and amide analogs of the parent compounds. The prodrug isformulated with the objectives of improved chemical stability, improvedpatient acceptance and compliance, improved bioavailability, prolongedduration of action, improved organ selectivity, improved formulation(e.g., increased hydrosolubility), and/or decreased side effects (e.g.,toxicity). In general, prodrugs themselves have weak or no biologicalactivity and are stable under ordinary conditions. Prodrugs can bereadily prepared from the parent compounds using methods known in theart, such as those described in A Textbook of Drug Design andDevelopment, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach,1991, particularly Chapter 5: “Design and Applications of Prodrugs”;Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs:Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker,1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, AcademicPress, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry andDrug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995,particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as NovelDelivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,1987, each of which is incorporated herein by reference in theirentireties.

The term “pharmaceutically acceptable prodrug” as used herein means aprodrug of a compound of the invention which is, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible.

The term “salt” means an ionic form of the parent compound or theproduct of the reaction between the parent compound with a suitable acidor base to make the acid salt or base salt of the parent compound. Saltsof the compounds of the present invention can be synthesized from theparent compounds which contain a basic or acidic moiety by conventionalchemical methods. Generally, the salts are prepared by reacting the freebase or acid parent compound with stoichiometric amounts or with anexcess of the desired salt-forming inorganic or organic acid or base ina suitable solvent or various combinations of solvents.

The term “pharmaceutically acceptable salt” means a salt of a compoundof the invention which is, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, generally water oroil-soluble or dispersible, and effective for their intended use. Theterm includes pharmaceutically-acceptable acid addition salts andpharmaceutically-acceptable base addition salts. As the compounds of thepresent invention are useful in both free base and salt form, inpractice, the use of the salt form amounts to use of the base form.Lists of suitable salts are found in, e.g., S. M. Birge et al., J.Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated byreference in its entirety.

The term “pharmaceutically-acceptable acid addition salt” means thosesalts which retain the biological effectiveness and properties of thefree bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoricacid, and the like, and organic acids such as acetic acid,trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonicacid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid,glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid,heptanoic acid, hexanoic acid, formic acid, fumaric acid,2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleicacid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid,mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid,nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid,pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid,pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylicacid, stearic acid, succinic acid, sulfanilic acid, tartaric acid,p-toluenesulfonic acid, undecanoic acid, and the like.

The term “pharmaceutically-acceptable base addition salt” means thosesalts which retain the biological effectiveness and properties of thefree acids and which are not biologically or otherwise undesirable,formed with inorganic bases such as ammonia or hydroxide, carbonate, orbicarbonate of ammonium or a metal cation such as sodium, potassium,lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum,and the like. Particularly preferred are the ammonium, potassium,sodium, calcium, and magnesium salts. Salts derived frompharmaceutically-acceptable organic nontoxic bases include salts ofprimary, secondary, and tertiary amines, quaternary amine compounds,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion-exchange resins, such as methylamine,dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine,isopropylamine, tripropylamine, tributylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine,choline, betaine, ethylenediamine, glucosamine, methylglucamine,theobromine, purines, piperazine, piperidine, N-ethylpiperidine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, N,N′-dibenzylethylenediamine, polyamine resins, and thelike. Particularly preferred organic nontoxic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline,and caffeine.

The term “solvate” means a physical association of a compound with oneor more solvent molecules or a complex of variable stoichiometry formedby a solute (for example, a compound of Formula (I)) and a solvent, forexample, water, ethanol, or acetic acid. This physical association mayinvolve varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances, the solvate will be capable ofisolation, for example, when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. Ingeneral, the solvents selected do not interfere with the biologicalactivity of the solute. Solvates encompasses both solution-phase andisolatable solvates. Representative solvates include hydrates,ethanolates, methanolates, and the like.

The term “hydrate” means a solvate wherein the solvent molecule(s)is/are H₂O.

The compounds of the present invention as discussed below include thefree base or acid thereof, their salts, solvates, and prodrugs and mayinclude oxidized sulfur atoms or quaternized nitrogen atoms in theirstructure, although not explicitly stated or shown, particularly thepharmaceutically acceptable forms thereof. Such forms, particularly thepharmaceutically acceptable forms, are intended to be embraced by theappended claims.

C. Isomer Terms and Conventions

The term “isomers” means compounds having the same number and kind ofatoms, and hence the same molecular weight, but differing with respectto the arrangement or configuration of the atoms in space. The termincludes stereoisomers and geometric isomers.

The terms “stereoisomer” or “optical isomer” mean a stable isomer thathas at least one chiral atom or restricted rotation giving rise toperpendicular dissymmetric planes (e.g., certain biphenyls, allenes, andspiro compounds) and can rotate plane-polarized light. Becauseasymmetric centers and other chemical structure exist in the compoundsof the invention which may give rise to stereoisomerism, the inventioncontemplates stereoisomers and mixtures thereof. The compounds of theinvention and their salts include asymmetric carbon atoms and maytherefore exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. Typically, such compounds will beprepared as a racemic mixture. If desired, however, such compounds canbe prepared or isolated as pure stereoisomers, i.e., as individualenantiomers or diastereomers, or as stereoisomer-enriched mixtures. Asdiscussed in more detail below, individual stereoisomers of compoundsare prepared by synthesis from optically active starting materialscontaining the desired chiral centers or by preparation of mixtures ofenantiomeric products followed by separation or resolution, such asconversion to a mixture of diastereomers followed by separation orrecrystallization, chromatographic techniques, use of chiral resolvingagents, or direct separation of the enantiomers on chiralchromatographic columns. Starting compounds of particularstereochemistry are either commercially available or are made by themethods described below and resolved by techniques well-known in theart.

The term “enantiomers” means a pair of stereoisomers that arenon-superimposable mirror images of each other.

The terms “diastereoisomers” or “diastereomers” mean optical isomerswhich are not mirror images of each other.

The terms “racemic mixture” or “racemate” mean a mixture containingequal parts of individual enantiomers.

The term “non-racemic mixture” means a mixture containing unequal partsof individual enantiomers.

The term “geometrical isomer” means a stable isomer which results fromrestricted freedom of rotation about double bonds (e.g., cis-2-buteneand trans-2-butene) or in a cyclic structure (e.g.,cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Becausecarbon-carbon double (olefinic) bonds, C═N double bonds, cyclicstructures, and the like may be present in the compounds of theinvention, the invention contemplates each of the various stablegeometric isomers and mixtures thereof resulting from the arrangement ofsubstituents around these double bonds and in these cyclic structures.The substituents and the isomers are designated using the cis/transconvention or using the E or Z system, wherein the term “E” means higherorder substituents on opposite sides of the double bond, and the term“Z” means higher order substituents on the same side of the double bond.A thorough discussion of E and Z isomerism is provided in J. March,Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4thed., John Wiley & Sons, 1992, which is hereby incorporated by referencein its entirety. Several of the following examples represent single Eisomers, single Z isomers, and mixtures of E/Z isomers. Determination ofthe E and Z isomers can be done by analytical methods such as x-raycrystallography, ¹H NMR, and ¹³C NMR.

Some of the compounds of the invention can exist in more than onetautomeric form. As mentioned above, the compounds of the inventioninclude all such tautomers.

It is well-known in the art that the biological and pharmacologicalactivity of a compound is sensitive to the stereochemistry of thecompound. Thus, for example, enantiomers often exhibit strikinglydifferent biological activity including differences in pharmacokineticproperties, including metabolism, protein binding, and the like, andpharmacological properties, including the type of activity displayed,the degree of activity, toxicity, and the like. Thus, one skilled in theart will appreciate that one enantiomer may be more active or mayexhibit beneficial effects when enriched relative to the otherenantiomer or when separated from the other enantiomer. Additionally,one skilled in the art would know how to separate, enrich, orselectively prepare the enantiomers of the compounds of the inventionfrom this disclosure and the knowledge of the prior art.

Thus, although the racemic form of drug may be used, it is often lesseffective than administering an equal amount of enantiomerically puredrug; indeed, in some cases, one enantiomer may be pharmacologicallyinactive and would merely serve as a simple diluent. For example,although ibuprofen had been previously administered as a racemate, ithas been shown that only the S-isomer of ibuprofen is effective as ananti-inflammatory agent (in the case of ibuprofen, however, although theR-isomer is inactive, it is converted in vivo to the S-isomer, thus, therapidity of action of the racemic form of the drug is less than that ofthe pure S-isomer). Furthermore, the pharmacological activities ofenantiomers may have distinct biological activity. For example,S-penicillamine is a therapeutic agent for chronic arthritis, whileR-penicillamine is toxic. Indeed, some purified enantiomers haveadvantages over the racemates, as it has been reported that purifiedindividual isomers have faster transdermal penetration rates compared tothe racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.

Thus, if one enantiomer is pharmacologically more active, less toxic, orhas a preferred disposition in the body than the other enantiomer, itwould be therapeutically more beneficial to administer that enantiomerpreferentially. In this way, the patient undergoing treatment would beexposed to a lower total dose of the drug and to a lower dose of anenantiomer that is possibly toxic or an inhibitor of the otherenantiomer.

Preparation of pure enantiomers or mixtures of desired enantiomericexcess (ee) or enantiomeric purity are accomplished by one or more ofthe many methods of (a) separation or resolution of enantiomers, or (b)enantioselective synthesis known to those of skill in the art, or acombination thereof. These resolution methods generally rely on chiralrecognition and include, for example, chromatography using chiralstationary phases, enantioselective host-guest complexation, resolutionor synthesis using chiral auxiliaries, enantioselective synthesis,enzymatic and nonenzymatic kinetic resolution, or spontaneousenantioselective crystallization.

Such methods are disclosed generally in Chiral Separation Techniques: APractical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R. P. W. Scott, Chiral Chromatography, John Wiley & Sons,1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am.Chem. Soc., 2000. Furthermore, there are equally well-known methods forthe quantitation of enantiomeric excess or purity, for example, GC,HPLC, CE, or NMR, and assignment of absolute configuration andconformation, for example, CD ORD, X-ray crystallography, or NMR.

In general, all tautomeric forms and isomeric forms and mixtures,whether individual geometric isomers or stereoisomers or racemic ornon-racemic mixtures, of a chemical structure or compound is intended,unless the specific stereochemistry or isomeric form is specificallyindicated in the compound name or structure.

D. Pharmaceutical Administration and Diagnostic and Treatment Terms andConventions

The term “patient” includes both human and non-human mammals.

The term “effective amount” means an amount of a compound according tothe invention which, in the context of which it is administered or used,is sufficient to achieve the desired effect or result. Depending on thecontext, the term effective amount may include or be synonymous with apharmaceutically effective amount or a diagnostically effective amount.

The terms “pharmaceutically effective amount” or “therapeuticallyeffective amount” means an amount of a compound according to theinvention which, when administered to a patient in need thereof, issufficient to effect treatment for disease-states, conditions, ordisorders for which the compounds have utility. Such an amount would besufficient to elicit the biological or medical response of a tissue,system, or patient that is sought by a researcher or clinician. Theamount of a compound of according to the invention which constitutes atherapeutically effective amount will vary depending on such factors asthe compound and its biological activity, the composition used foradministration, the time of administration, the route of administration,the rate of excretion of the compound, the duration of treatment, thetype of disease-state or disorder being treated and its severity, drugsused in combination with or coincidentally with the compounds of theinvention, and the age, body weight, general health, sex, and diet ofthe patient. Such a therapeutically effective amount can be determinedroutinely by one of ordinary skill in the art having regard to their ownknowledge, the prior art, and this disclosure.

The term “diagnostically effective amount” means an amount of a compoundaccording to the invention which, when used in a diagnostic method,apparatus, or assay, is sufficient to achieve the desired diagnosticeffect or the desired biological activity necessary for the diagnosticmethod, apparatus, or assay. Such an amount would be sufficient toelicit the biological or medical response in a diagnostic method,apparatus, or assay, which may include a biological or medical responsein a patient or in a in vitro or in vivo tissue or system, that issought by a researcher or clinician. The amount of a compound accordingto the invention which constitutes a diagnostically effective amountwill vary depending on such factors as the compound and its biologicalactivity, the diagnostic method, apparatus, or assay used, thecomposition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of administration, drugs and other compounds used incombination with or coincidentally with the compounds of the invention,and, if a patient is the subject of the diagnostic administration, theage, body weight, general health, sex, and diet of the patient. Such adiagnostically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, theprior art, and this disclosure.

The term “modulate” means the ability of a compound to alter thefunction of the glucocorticoid receptor by, for example, binding to andstimulating or inhibiting the glucocorticoid receptor functionalresponses.

The term “modulator” in the context of describing compounds according tothe invention means a compound that modulates the glucocorticoidreceptor function. As such, modulators include, but are not limited to,agonists, partial agonists, antagonists, and partial antagonists.

The term “agonist” in the context of describing compounds according tothe invention means a compound that, when bound to the glucocorticoidreceptor, enhances or increases the glucocorticoid receptor function. Assuch, agonists include partial agonists and full agonists.

The term “full agonist” in the context of describing compounds accordingto the invention means a compound that evokes the maximal stimulatoryresponse from the glucocorticoid receptor, even when there are spare(unoccupied) glucocorticoid receptors present.

The term “partial agonist” in the context of describing compoundsaccording to the invention means a compound that is unable to evoke themaximal stimulatory response from the glucocorticoid receptor, even atconcentrations sufficient to saturate the glucocorticoid receptorspresent.

The term “antagonist” in the context of describing compounds accordingto the invention means a compound that directly or indirectly inhibitsor suppresses the glucocorticoid receptor function. As such, antagonistsinclude partial antagonists and full antagonists.

The term “full antagonist” in the context of describing compoundsaccording to the invention means a compound that evokes the maximalinhibitory response from the glucocorticoid receptor, even when thereare spare (unoccupied) glucocorticoid receptors present.

The term “partial antagonist” in the context of describing compoundsaccording to the invention means a compound that is unable to evoke themaximal inhibitory response from the glucocorticoid receptor, even atconcentrations sufficient to saturate the glucocorticoid receptorspresent.

The terms “treating” or “treatment” mean the treatment of adisease-state in a patient, and include:

-   -   (i) preventing the disease-state from occurring in a patient, in        particular, when such patient is genetically or otherwise        predisposed to the disease-state but has not yet been diagnosed        as having it;    -   (ii) inhibiting or ameliorating the disease-state in a patient,        i.e., arresting or slowing its development; or    -   (iii) relieving the disease-state in a patient, i.e., causing        regression or cure of the disease-state.        General Synthetic Methods for Making Compounds of Formula (IA)        and Formula (IB)

The invention also provides processes for making compounds of Formula(IA) and Formula (IB). In all schemes, unless specified otherwise, R¹ toR⁵ in the formulas below shall have the meaning of R¹ to R⁵ in theFormula (IA) of the invention described hereinabove; and whereappropriate, R¹ to R⁶ in the formulas below shall have the meaning of R¹to R⁶ in the Formula (IB) of the invention described hereinabove.Intermediates used in the preparation of compounds of the invention areeither commercially available or readily prepared by methods known tothose skilled in the art.

Optimum reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Experimental Examples section. Typically, reactionprogress may be monitored by thin layer chromatography (TLC), ifdesired, and intermediates and products may be purified bychromatography on silica gel and/or by recrystallization.

Compounds of Formula (I) may be prepared by the method outlined inScheme I.

As illustrated in Scheme I, an ester intermediate of Formula (II) whereR′ is Me or Et, is reduced with a suitable reducing agent, such aslithium aluminum hydride, in a suitable solvent, such as THF or diethylether, to produce the 1,2-diol of Formula (III). Oxidative cleavage of1,2-diols is well-known in the art and may be achieved with periodicacid or lead tetraacetate, for example, in a suitable solvent, such asmethanol, to provide the ketone (IV). Reaction of ketone (IV) with asuitable organometallic reagent R⁵R⁴M, such as a Grignard reagent (M isMgBr or MgCl) or an organolithium reagent (M is Li), in a suitablesolvent such as THF or diethyl ether provides the desired compound ofFormula (I). Such organolithium reagents and alkylmagnesium halides orGrignard reagents are well-known in the art, for example, Grignardreagents are easily prepared by reacting the corresponding alkyl halidewith magnesium metal in a suitable solvent, such as ether or THF, underanhydrous conditions.

Scheme II outlines another approach that may be used to obtain compoundsof Formula (I).

In Scheme II, the hydroxyl function on intermediate (II) is protected toprovide ester (V). Hydroxyl protecting groups are well-known in the art,an example of a suitable protecting group is a methoxymethyl ether.Reduction of the ester (V) with a suitable reducing agent such aslithium aluminum hydride provides alcohol (VI). Oxidation of alcohol(VI) with an oxidizing agent such as pyridinium chlorochromate (PCC)provides aldehyde (VII). Treatment of aldehyde (VII) with a suitableorganometallic reagent R⁵M where M is Li or MgX, and X is Cl, Br, or I,that is, an organolithium reagent or Grignard reagent or alkylmagnesiumhalide bearing R⁵, provides alcohol (VIII). Deprotection by standardmethods, which would depend on the protecting group used, gives thedesired compound of Formula (I) where R⁴ is —CH(OH)—. Oxidation ofalcohol (VIII) to (IX) with an oxidizing agent such as PCC or1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one, followed bydeprotection provides the desired compound of Formula (I) where R⁴ is—C(O)—.

Compounds of Formula (I) may also be prepared by the method outlined inScheme III.

In this approach, trifluoroacetic anhydride andN,O-dimethylhydroxylamine hydrochloride are coupled under basicconditions to afford trifluoroacetamide (X) (Weinreb amide). The Weinrebamide (X) is reacted with a vinyl magnesium bromide bearing R² and R³ toafford the trifluoromethylenone intermediate (XI). Thetrifluoromethylenone intermediate (XI) is treated with an organocopperreagent, derived from a Grignard or organolithium reagent by treatingwith a copper salt, to afford the 1,4-addition product (IV). Thistrifluoro ketone intermediate (IV) is reacted with an organometallicreagent R⁴R⁵M (as described in Scheme I) to afford the desired compoundof Formula (I).

Compounds of Formula (I) in which R⁴-R⁵ is an optionally substitutedbenzimidazol-2-ylmethyl group may also be prepared by the procedureoutlined in Scheme IV.

As illustrated in Scheme IV, trifluoromethyl ketone (IV) is reacted withethyl acetate in the presence of a strong base such as lithiumdiisopropylamide (LDA) in a suitable solvent such as THF. Theintermediate ester is hydrolyzed, for example, by treatment with aqueousbase, to provide carboxylic acid intermediate (XII). This carboxylicacid intermediate (XII) is then coupled with an optionally substitutedo-phenylenediamine under standard coupling conditions known in the art,for example, by treatment with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) in the presence of1-hydroxybenzotriazole in a suitable solvent such as DMF, to providecompound (XIII). Ring closure by methods known in the art, for example,acid catalyzed ring closure by treatment with polyphosphoric acid,provides the desired compound of Formula (I).

Compounds of Formula (IB) may be prepared by the procedure illustratedin Scheme V.

In Scheme V, substituted phenol (XIV) is reacted with an acryloylchloride bearing R² and R³ (XV) in the presence of a suitable base, suchas triethylamine, to provide an intermediate ester which is cyclized bytreatment with a Lewis acid, such as aluminum trichloride, in a suitablesolvent, such as carbon disulfide, to provide lactone (XVI). The lactone(XVI) is treated with a suitable amine HNR″R′″, such as morpholine, suchthat in the resulting amide (XVII), —NR″R′″ will function as a leavinggroup in the subsequent reaction. The intermediate phenol that forms isprotected, for example, by reaction with methyl iodide in the presenceof a suitable base such as potassium hydroxide to form the protectedphenol (XVII), in this case having a methoxy group. The amide is thenreacted with an organometallic reagent (R⁶M), such as a Grignard reagent(M is MgBr or MgCl) or an organolithium reagent (M is Li), in a suitablesolvent, such as THF or diethyl ether, to provide the ketone (XVIII).Reaction of the ketone (XVIII) with R⁵R⁴M as described in the last stepin Scheme I provides the desired compound of Formula (IB) where R¹ is anoptionally substituted methoxyphenyl group.

In a more general procedure, suitable for a variety of R¹, one may use amethod analogous to that described in Scheme III. As illustrated inScheme VI, using a Weinreb amide bearing R⁶ one may employ the methoddescribed in Scheme III to prepare the desired compound of Formula (IB).

An alternative method to prepare intermediate (IV), used in the methodsillustrated in Schemes I-IV, is illustrated in Scheme VII.

In Scheme VII, a ketone bearing R¹ and R² (XIX) is reacted with acyanoacetic acid ester, such as the methyl ester (XX) under condensationconditions known in the art to provide the olefin (XXI). Reaction ofolefin (XXI) with R³Li in the presence of a copper salt such as CuIprovides compound (XXII). Hydrolysis and decarboxylation of compound(XXII) results in nitrile (XXIII). Reduction of nitrile (XXIII), forexample, by treatment with diisobutylaluminum hydride (DIBAL), providesaldehyde (XXIV). Treatment of aldehyde (XXIV) withtrimethyl(trifluoromethyl)silane in the presence of an ammonium saltsuch as tetrabutylammonium fluoride provides alcohol (XXV). Oxidation ofalcohol (XXV) by methods known in the art, such as by treatment with theDess-Martin periodinane, provides compound (IV).

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating embodiments of this invention, and are not to be construedas limiting the scope of the invention in any way since, as recognizedby one skilled in the art, particular reagents or conditions could bemodified as needed for individual compounds. Starting materials used areeither commercially available or easily prepared from commerciallyavailable materials by those skilled in the art.

EXPERIMENTAL EXAMPLES Example 1 Synthesis of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-phenylbenzoxazol-2-ylmethyl)pentan-2-ol

To a mixture of 8.5 g (49.9 mmol) of ethyl trifluoromethylpyruvate, 6.6g (120 mmol) of manganese, and 0.65 g (4.8 mmol) of zinc chloride in 40mL of THF warmed to reflux was added 200 μL (2 mmol) of1-bromo-2-methylpropene. After 30 minutes, 9.13 mL (90.5 mmol) of1-bromo-2-methylpropene in 30 mL of THF was added dropwise over a 1 hourperiod. The mixture was refluxed for 1 hour after the addition and wasthen cooled to 0° C. and diluted with 150 mL of saturated aqueousammonium chloride and 100 mL of EtOAc. The organic phase was separatedand the aqueous layer extracted with three 100 mL portions of EtOAc. Thecombined organic layers were washed with two 50 mL portions of saturatedaqueous ammonium chloride, followed by two 50 mL portions of brine,dried over magnesium sulfate (MgSO₄), filtered, and concentrated invacuo. The crude residue was purified by silica gel chromatographyeluting with EtOAc-hexanes (5:95) to afford 5.9 g (52%) of2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester.

To a mixture of 5.9 g (26.1 mmol) of the above2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester in 30mL of 4-fluoroanisole was added in several portions 5.2 g (39.4 mmol) ofaluminum chloride. The mixture became exothermic and turned black withthe first addition and was cooled with an ice-water bath. The mixturewas stirred for 3 days and was then poured into 200 mL of ice-cold 1 Naqueous HCl and extracted with three 150 mL portions of EtOAc. Thecombined organic layers were washed with 50 mL of 1 N aqueoushydrochloric acid, three 50 mL portions of brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude residue waspurified by silica gel chromatography eluting with EtOAc-hexanes (1:9,then 2:8, then 3:7, then 4:6) to afford 6.6 g (71%) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoicacid ethyl ester.

To a chilled solution (ice-water bath) of 6 g (17.0 mmol) of the above4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoicacid ethyl ester in 60 mL of dry THF, 2.4 g (61.5 mmol) of lithiumaluminum hydride was added in portions. After the addition, the coldbath was removed and the mixture was stirred at room temperatureovernight. The mixture was then warmed to reflux for 3 hour and thencautiously quenched by slow addition to 100 mL of THF containing 2 mL ofwater. Additional water was then cautiously added for a total of 15 mLand the resulting mixture stirred for 2 hours. The excess water wasdried over magnesium sulfate and 300 mL of EtOAc was added. After 1hour, the mixture was filtered through diatomaceous earth andconcentrated in vacuo to afford 4.9 g (92%) of4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diolas an oil.

To a solution of 4.9 g (15.8 mmol) of the above4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diolin 100 mL of MeOH was added 10 g (45.9 mmol) of sodium periodate. Themixture was stirred for 4 hours and was then diluted with 100 mL ofether and 100 mL of hexanes, filtered through diatomaceous earth, andconcentrated in vacuo. The crude residue was dissolved in hexanes andpassed through a pad of silica gel eluting first with hexanes then withEtOAc-hexanes (2:98, then 4:96) to afford 3.85 g (87%) of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as aclear oil.

n-Butyl lithium (0.246 mL, 1.6 M in hexanes) was added to a solution ofdiisopropyl amine (0.055 mL, 0.45 mmol) in anhydrous THF (5 mL) at 0° C.The reaction mixture was cooled to −78° C. and stirred for 15 minutes.2-Methyl-5-phenyl benzoxazole (75 mg, 0.4 mmol) dissolved in anhydrousTHF (2 mL) was added to this mixture dropwise. After the addition, thereaction mixture was stirred for 15 to 30 minutes.1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100mg, 0.4 mmol) was added as a solution in anhydrous THF (2 mL) in oneportion, the cold bath was removed and the reaction was stirred at roomtemperature for 12 hours. THF was evaporated under reduced pressure.Water (2 mL) was added to the residue and the mixture was extracted withthree 5 mL portions of EtOAc. The extract was dried over magnesiumsulfate. After evaporation, the residue was chromatographed on a silicagel column to provide 150 mg of the title compound as white crystals,m.p. 103° C.-104° C.

Example 2 Synthesis of2-benzoxazol-2-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

n-Butyl lithium (0.246 mL, 1.6 M in hexanes) was added to a solution ofdiisopropyl amine (0.055 mL, 0.45 mmol) in anhydrous THF (5 mL) at 0° C.The reaction mixture was cooled to −78° C. and stirred for 15 minutes. Asolution of 2-methylbenzofuran (48 mg, 0.4 mmol) in 2 mL anhydrous THFwas added dropwise to this mixture. After the addition, the reactionmixture was stirred for 15 to 30 minutes.1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4methylpentan-2-one (100mg, 0.4 mmol) (Example 1) was added as a solution in anhydrous THF (2mL) in one portion, the cold bath was removed, and the reaction wasstirred at room temperature for 12 hours. THF was evaporated underreduced pressure. Water (2 mL) was added to the residue and the mixturewas extracted with three 5 mL portions of EtOAc. The extract was driedover magnesium sulfate. After evaporation, the residue waschromatographed on a silica gel column to provide 86 mg of the titlecompound as an oil.

Example 3 Synthesis of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methylbenzofuran-2-ylmethyl)pentan-2-ol

n-Butyl lithium (0.246 mL, 1.6 M in hexanes) was added to a solution ofdiisopropyl amine (0.055 mL, 0.45 mmol) in anhydrous THF (5 mL) at 0° C.The reaction mixture was cooled to −78° C. and stirred for 15 minutes. Asolution of 2,3-dimethylbenzofuran (48 mg, 0.4 mmol) in 2 mL anhydrousTHF was added dropwise to this mixture. After the addition, the reactionmixture was stirred for 15 to 30 minutes.1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100mg, 0.4 mmol) (Example 1) was added as a solution in anhydrous THF (2mL) in one portion, the cold bath was removed, and the reaction wasstirred at room temperature for 12 hours. THF was evaporated underreduced pressure. Water (2 mL) was added to the residue and the mixturewas extracted with three 5 mL portions of EtOAc. The extract was driedover magnesium sulfate. After evaporation, the residue waschromatographed on a silica gel column to provide 80 mg of the titlecompound as an oil.

Example 4 Synthesis of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol

n-Butyl lithium (0.673 mL, 1.6 M in hexanes) followed by potassiumtert-butoxide (81 mg, 0.718 mmol) was added to a stirred solution of2-methyl indole (47 mg, 0.359 mmol) in anhydrous diethyl ether (5 mL) atroom temperature. Within 5 to 10 minutes, the reaction mixture turnedbright orange.1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100mg, 0.4 mmol) (Example 1) was then added dropwise as a solution inanhydrous diethyl ether (2 mL). The reaction was quenched with waterafter 1 hour, extracted with three 5 mL portions of EtOAc, dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel affording 45 mg ofthe title compound as an oil.

Example 5 Synthesis of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(pyridin-2-ylmethyl)-4-methylpentan-2-ol

tert-Butyl lithium (1.7 M in pentane, 0.5 mL) was added dropwise to asolution of 2-methylpyridine (0.050 g) in THF (0.5 mL) cooled to −70° C.under argon. The mixture was stirred at −70° C. for 10 minutes and1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (0.080g) (Example 1) in THF (0.5 mL) was added over 1 minute. The reactionmixture was stirred for 5 minutes and then quenched with MeOH. Thereaction mixture was concentrated in vacuo and the residue fractionateddirectly by preparative layer chromatography on silica gel (methylenechloride-hexanes (1:1)) to give the 57 mg of the title compound, m.p.94° C.-96° C.

Example 6 Synthesis of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4,6-dimethylpyridin-2-ylmethyl)-4-methylpentan-2-ol

tert-Butyl lithium (1.7 M in pentane, 0.5 mL) was added dropwise to asolution of 2,4,6-trimethylpyridine (0.12 g) in THF (0.5 mL) cooled to−70° C. under argon. The mixture was stirred at −70° C. for 15 minutesand 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one(0.10 g) (Example 1) in THF (0.5 mL) was added. The reaction mixture wasstirred for 20 minutes and then quenched with acetic acid. The mixturewas diluted with EtOAc, washed with water, dried, filtered, andconcentrated in vacuo. Fractionation by preparative layer chromatographyon silica gel (methylene chloride-hexanes) followed by crystallizationgave 43 mg of the title compound, m.p. 95° C.-98° C.

Example 7 Synthesis of2-(2,6-dichloropyridin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

To a 100 mL dry round bottom flask was added 73 mg (3.0 mmol) ofmagnesium powder, a couple of I₂ crystals, and 5 mL of dry diethylether, and the mixture was allowed to stir under argon.4-Bromomethyl-2,6-dichloropyridine (723 mg, 3.0 mmol) in 10 mL ofdiethyl ether was added dropwise through a dropping funnel and theresulting mixture was heated to reflux for 1 hour.1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (278mg, 1.0 mmol) (Example 1) in diethyl ether (5 mL) was carefully addeddropwise through a dropping funnel and the mixture was allowed to stirto reflux temperature for 4 hours and then overnight (16 hours) at roomtemperature. The reaction was quenched with the addition of 3 mL ofaqueous NH₄Cl solution, and the resulting mixture was extracted withthree 30 mL portions of EtOAc, washed with H₂O (10 mL) and brine (10mL), and the organic phase was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel using an EtOAc-hexanes gradient. Combined productfractions were concentrated in vacuo to afford the desired product whichwas further purified by preparative-HPLC using a gradient of 80%-100%(CH₃CN-water) in 15 minutes and a flow rate of 20 mL/min to afford 76 mgof the title compound (17.2% yield) as a yellowish liquid.

Example 8 Synthesis of2-(5-chloro-7-fluoro-1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

A stirred suspension of zinc dust (0.656 g) and mercuric chloride (25mg) in 5 mL of anhydrous THF was cooled on ice. A solution oftrimethylsilyl-propargyl bromide (0.96 g, 5 mmol) in anhydrous THF (1mL) was added, the ice-bath was removed, and the reaction mixture wasstirred at room temperature for 20 hours. To solution of the resultingorganozinc reagent was added a solution of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (0.2g, 0.72 mmol) (Example 1) in anhydrous THF (1 mL) and the reactionmixture was stirred at room temperature for 4 hours. TLC (hexanes-EtOAc(95:5)) indicated consumption of starting material with a single morepolar spot. The reaction mixture was quenched with a saturated solutionof ammonium chloride. The resulting mixture was extracted with three 30mL portions of dichloromethane, the combined extracts were washed withtwo 20 mL portions of water, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The crude product was purified by columnchromatography over silica gel eluting with hexanes-EtOAc (95:5) to givethe desired alcohol intermediate as a colorless oil.

To a stirred solution of the above alcohol (200 mg, 0.51 mmol) inanhydrous THF (2 mL) cooled in ice was added 0.5 mL of 1 M solution oftetrabutylammonium fluoride solution in THF. After 30 minutes, TLC inhexanes-EtOAc (95:5) indicated consumption of starting material. Thereaction mixture was quenched with a saturated solution of ammoniumchloride (5 mL), extracted with ether (100 mL), washed with two 25 mLportions of water, dried over anhydrous sodium sulfate, and concentratedin vacuo, providing the desired terminal acetylene intermediate (160 mg,98%).

A mixture of the above acetylene intermediate (85 mg, 0.27 mmol),4-chloro-2-fluoro-6-iodoacetanilide (90 mg, 0.29 mmol),bis(triphenylphosphine)palladium(II) chloride catalyst (20 mg, 0.028mmol), copper (I) iodide (8 mg, 0.042 mmol), and tetramethylguanidine(0.2 mL) in anhydrous dioxane (0.5 mL) was stirred and heated in anoil-bath maintained at 80° C. for 20 hours. After cooling to roomtemperature, the reaction mixture was diluted with dichloromethane (25mL) and filtered through diatomaceous earth, which was then rinsed withdichloromethane. The filtrate and the washings were collected, washedwith three 20 mL portions of 1 N H₂SO₄, three 20 mL portions of water,dried over anhydrous sodium sulfate, and concentrated in vacuo to give abrownish oil. The crude product was purified by preparative TLC elutingwith hexanes-EtOAc (90:10). The band corresponding to R_(f) 0.26 wascollected, providing the title compound as an oil.

Example 9 Synthesis of2-(1H-benzimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

To a solution of 2-methylbenzimidazole (300 mg, 2.3 mmol) in 20 mL ofanhydrous THF at −30° C., n-butyl lithium (1.6 M in pentanes, 3 mL, 4.8mmol) was slowly added. The resulting red-colored heterogeneous mixturewas stirred for 2 hours at this temperature, then a solution of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (700mg, 2.55 mmol) (see Example 1) in anhydrous THF (1 mL) was addeddropwise. The reaction temperature was allowed to slowly warm to roomtemperature over a period of 2 hours, at which time reaction was treatedwith saturated NH₄Cl solution. The resulting mixture was extracted withdiethyl ether. The combined organic extracts were dried over magnesiumsulfate, filtered, and concentrated in vacuo to afford an oil which waspurified by chromatography on silica gel to provide 200 mg of unchanged2-methylbenzimidazole and 60 mg of the title compound as a white solid,m.p. 80° C.-82° C.

Example 10 Synthesis of2-(1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-ol

To a mixture of 15.8 g of N,O-dimethylhydroxylamine hydrochloride in 400mL of CH₂Cl₂, 21.7 mL of trifluoroacetic anhydride was added dropwise at0° C. Pyridine (37 mL) was then added to the above mixture dropwise at0° C. The resulting mixture was allowed to stir at 0° C. for 30 minutes,and was then quenched with water. The organic layer was washed withwater, 1 N aqueous HCl, water and brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was pumped under vacuumfor 5 minutes providing 2,2,2-trifluoro-N-methoxy-N-methylacetamide as acolorless oil.

A mixture of 3 g of 2,2,2-trifluoro-N-methoxy-N-methylacetamide and 30mL of anhydrous ether was cooled down to 0° C. and treated with 42 mL ofa 0.5 M solution of 2-methyl propenylmagnesium bromide in THF. Thereaction was stirred at 0° C. for 0.5 minutes and then warmed to roomtemperature and stirred overnight. The reaction was quenched withsaturated aqueous NH₄Cl and extracted with ether three times. Theorganic layers were combined and washed with water and brine, dried overmagnesium sulfate, and filtered. The resulting ether/THF solution of1,1,1-trifluoro-4-methylpent-3-en-2-one was used for the next reactionwithout further purification.

To a 2 M ether/THF solution of 1,1,1-trifluoro-4-methylpent-3-en-2-onewas added 3.8 g of copper (I) iodide and 10 mL of a 2 M ether solutionof 4-fluorophenylmagnesium bromide at 0° C. The mixture was warmed toroom temperature and stirred for 2 hours. The reaction was quenched withsaturated aqueous NH₄Cl, and extracted three times with EtOAc. Thecombined organic layers were washed with water, brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified by flash chromatography to yield 460 mg of1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-one.

To a diethyl ether solution of 53 mg of 2-methylindole was added 3equivalents of n-butyl lithium followed by 90 mg of potassiumtert-butoxide (t-BuOK) (solid) at room temperature. The mixture wasallowed to stir for 30 minutes.1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-one (100 mg) indiethyl ether was then added to the above mixture. The reaction wasstirred at room for 1 hour. The reaction was quenched with saturatedaqueous ammonium chloride, and extracted three times with EtOAc. Thecombined organic layers were washed with water, brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified by column chromatography to yield 40 mg of the title compoundas a foam. Resolution to the (+)- and (−) enantiomers was accomplishedby chiral HPLC on a CHIRALCEL® OD™ column, eluting with 10%isopropanol-hexanes.

The following compounds were made by procedures analogous to thosedescribed in Example 10.

-   1,1,1-Trifluoro-4-(3-fluorophenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   4-(3,4-Dichlorophenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;    and-   4-(3,4-Difluorophenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol.

Example 11 Synthesis of4-(4-chlorophenyl)-1,1,1-trifluoro-4-methyl-2-pyridin-2-ylmethylpentan-2-ol

A mixture of 2-picoline in 1 mL of THF was cooled down to −78° C.tert-Butyl lithium (1.7 M in pentanes, 0.2 mL (0.34 mmol)) was addeddropwise over 5 minutes. The mixture stirred at −78° C. for 15 minutes,and then a solution of 40 mg of4-(4-chlorophenyl)-1,1,1-trifluoro-4-methylpentan-2-one in 0.5 mL of THFwas added. Stirring continued at −78° C. for 20 minutes. The reactionwas quenched with 0.5 N HCl and extracted three times with EtOAc. Theorganic layers were combined and washed with water, brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified by column chromatography to yield 9.6 mg of the title compoundas a light yellowish oil.

Example 12 Synthesis of1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-pyridin-2-ylpentan-2-ol

A solution of 4.5 mL (9 mmol, 1.2 eq.) of oxalyl chloride (2.0 Msolution in dichloromethane) was diluted with 15 mL of dichloromethane.To this solution was added a solution of 1.2 mL (17.5 mmol, 2.4 eq.) ofDMSO in 3 mL of dichloromethane at −60° C. and the mixture was stirredfor 10 minutes at this temperature. To this mixture was added a solutionof 1 g (7.3 mmol) of 4-pyridinepropanol in 7 mL of dichloromethane at−60° C. The resulting mixture was stirred at −60° C. for 15 minutes,then 5.0 mL (36.5 mmol, 5.0 eq.) of triethylamine was added at thistemperature. The cooling bath was removed and the reaction mixture wasallowed to warm to room temperature and was quenched with water. Theorganic layer was separated and the aqueous layer was extracted threetimes with dichloromethane. The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified by flash chromatography providing 3-pyridin-2-ylpropionaldehydeas a brown oil.

Yield: 769 mg (78%).

A solution of 760 mg (5.6 mmol) of 3-pyridin-2-ylpropionaldehyde in 3 mLof THF was treated with 13.6 mL (6.8 mmol, 1.2 eq.) oftrimethyl(trifluoromethyl)silane (0.5 M solution in THF) and 0.06 mL(0.06 mmol) of tetrabutylammonium fluoride (1.0 M solution in THF) at 0°C. The resulting mixture was stirred at 0° C. for 10 minutes, andquenched with 1 N HCl solution. After stirring for 5 minutes, the pH ofthe reaction mixture was adjusted to 9 with saturated NaHCO₃ solution,and the product was extracted into ether. The ethereal layer was washedwith water and brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyto give 706 mg (61%) of 1,1,1-trifluoro-4-pyridin-2-ylbutan-2-ol as acolorless oil.

A solution of 700 mg (3.4 mmol) of1,1,1-trifluoro-4-pyridin-2-ylbutan-2-ol in 10 mL of dichloromethane wastreated with 616 mg (4.1 mmol, 1.2 eq.) of tert-butyldimethylsilylchloride, 697 mg (10.2 mmol, 3.0 eq.) of imidazole and 415 ng (3.4 mmol)of 4-dimethylaminopyridine at 0° C. The resulting mixture was allowed towarm to room temperature and was stirred for 36 hours. Then the mixturewas concentrated and the residue was purified by flash chromatography togive 970 mg (89%) of2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluorobutyl]pyridine as acolorless oil.

A solution of 810 mg (2.54 mmol) of2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluorobutyl]pyridine in 8mL of THF was treated with 2.54 mL (3.81 mmol, 1.5 eq.) of LDA (1.5 Msolution in cyclohexane) at −75° C. After stirring at −75° C. for 45minutes, 474 μL (7.61 mmol, 3.0 eq.) of methyl iodide was added at −75°C. The resulting mixture was stirred at this temperature for 10 minutesand quenched with saturated NH₄Cl solution. The product was extractedinto ether. The ethereal layer was washed with water, brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo to give 750 mg(89%) of2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1-methylbutyl]pyridine(a mixture of two diastereomers) as a brown oil.

To a solution of 3.87 mL (3.87 mmol, 1.5 eq.) of potassium tert-butoxide(1.0 M solution in THF) and 542 μL (3.87 mmol, 1.5 eq.) ofdiisopropylamine, 1.55 mL (3.87 mmol, 1.5 eq) of n-butyl lithium (2.5 Msolution in hexanes) was added dropwise at −75° C. The resulting mixturewas allowed to warm to −50° C. over 15 minutes. Then the reactionmixture was treated with 860 mg (2.58 mmol) of2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1-methylbutyl]pyridineat −50° C. and the resulting mixture was stirred for 30 minutes at −50°C. The reaction mixture was cooled to −75° C. and treated with 482 μL(7.74 mmol) of methyl iodide and stirred for 1 minute. The reactionmixture was quenched with saturated NH₄Cl solution and the product wasextracted into ether. The ethereal layer was washed with water andbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified by flash chromatography to give 555 mg(62%) of2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]pyridineas a colorless oil.

A mixture of 550 mg (1.58 mmol) of2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]pyridinein 4.5 mL (4.5 mmol) of tetrabutylammonium fluoride (1.0 M solution inTHF) was stirred at room temperature for 2 hours. The mixture wasconcentrated in vacuo and the residue was purified by flashchromatography to give 367 mg (99%) of1,1,1-trifluoro-4-methyl-4-pyridin-2-ylpentan-2-ol as a light yellowoil.

A solution of 516 μL (1.03 mmol, 1.2 eq) of oxalyl chloride (2.0 Msolution in dichloromethane) was diluted with 2 mL of dichloromethane.To this solution was added a solution of 146 μL (2.06 mmol, 2.4 eq.) ofDMSO in 0.2 mL of dichloromethane at −60° C. and the mixture was stirredfor 10 minutes at this temperature. Then to this mixture was added asolution of 200 mg (0.86 mmol) of1,1,1-trifluoro-4-methyl-4-pyridin-2-ylpentan-2-ol in 2 mL ofdichloromethane at −60° C. The resulting mixture was stirred at −60° C.for 15 minutes and then 600 μL (4.3 mmol, 5.0 eq.) of triethylamine wasadded. The cooling bath was removed and the reaction mixture was allowedto warm to room temperature and quenched with water. The organic layerwas separated. The aqueous layer was extracted three times withdichloromethane. The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby flash chromatography, providing 172 mg (86%)1,1,1-trifluoro-4-methyl-4-pyridin-2-ylpentan-2-one as a brown oil.

To a solution of 42.4 mg (0.324 mmol, 1.5 eq.) of 2-methylindole in 2 mLof THF, 389 μL (0.972 mmol, 4.5 eq.) of n-butyl lithium (2.5 M solutionin hexanes) and 648 μL (0.648 mmol, 3.0 eq.) of potassium tert-butoxide(1.0 M solution in THF) were added dropwise at −75° C. The resultingmixture was allowed to warm to −20° C. over 30 minutes. The reactionmixture was cooled to −75° C. and a solution of 50 mg (0.216 mmol) of1,1,1-trifluoro-4-methyl-4-pyridin-2-ylpentan-2-one in 1 mL of THF wasadded at this temperature. The resulting mixture was stirred at thistemperature for 30 minutes and then quenched with saturated NH₄Clsolution. The product was extracted into ether and the ethereal layerwas washed with water and brine, dried over magnesium sulfate, filtered,and concentrated in vacuo. The residue was purified by flashchromatography to give 22 mg (28%) of the title compound as a whitefoam.

Example 13 Synthesis of7-(5-fluoro-2-methoxyphenyl)-5-(indol-2-ylmethyl)-7-methyloctan-5-ol

To a solution of 4-fluorophenol (11.2 g) and dimethylacryloyl chloride(11.9 g) in diethyl ether (200 mL) cooled on ice, triethylamine (14 mL)was added dropwise over 20 minutes. After an additional 30 minutes thereaction mixture was filtered through diatomaceous earth to removeprecipitated triethylamine hydrochloride. The ether solution was washedwith water and brine, dried over sodium sulfate and evaporated to givecrude intermediate ester (19 g). The ester was dissolved in carbondisulfide (50 mL) and aluminum trichloride (19 g) was added slowly as asolid over 1 hour (exothermic reaction). The mixture was then allowed tostir at room temperature overnight. The carbon disulfide was removed ina stream of nitrogen. The residue was quenched by pouring onto ice andneutralized with aqueous sodium bicarbonate. The mixture was extractedwith ether, and the organic phase was dried, filtered and evaporated.Chromatography of the residue over a column of silica gel topped withFLORISIL® activated magnesium silicate packing (eluent: ether-hexanes(95:5)) gave the desired lactone as an oil that solidified ontrituration with a little hexanes (yield: 10.5 g).

The lactone and morpholine were heated at 80° C. (bath temperature) for30 minutes. Crystalline product appeared. The mixture was cooled to roomtemperature and triturated with water. The crystalline product wascollected by filtration. The product was taken up in DMSO (20 mL) andmethyl iodide (2 mL) was added. A solution of potassium hydroxide (1.2g) in water (10 mL) was added over 20 minutes (moderate exotherm).Additional methyl iodide was added (0.5 mL) followed by potassiumhydroxide (0.25 g) in water (5 mL). The mixture was stirred for 20minutes. The crystalline product was collected by filtration, washedwith water and dried under vacuum at 40° C. to give3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (5.1g).

To a solution of the above3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.29g) in THF (2 mL) cooled to −70° C. under argon was added dropwise over 5minutes n-butyl lithium (2 M in pentane, 1 mL). The mixture was stirredat −70° C. for 15 minutes and then quenched with EtOH (0.2 mL). Water (1mL) and EtOAc (2 mL) were added and the mixture was warmed to roomtemperature. The organic phase was separated and washed with water,dried over sodium sulfate, filtered, and evaporated to give the productas an oil (0.26 g).

To a solution of 2-methylindole (0.13 g) in THF (1 mL) cooled to −70° C.under argon was added n-butyl lithium (2.5 M in hexane, 1.3 mL)dropwise. After 5 minutes, potassium tert-butoxide (1M in THF, 2 mL) wasadded and the cooling bath was removed. After about 5 minutes, a solidprecipitate appeared and the mixture was re-cooled on a dry ice/acetonebath. The ketone from above (0.24 g) in THF (1 mL) was added all at onceand the mixture was stirred warming to room temperature over 1 hour. Thereaction was quenched with EtOH (0.3 mL) and diluted with EtOAc. Themixture was washed with water, dried, filtered and evaporated.Preparative layer chromatography of the residue (developer methylenechloride) followed by a second preparative layer chromatography(developer: EtOAc-hexanes (5:95)) gave the title compound as an oil (24mg).

Examples 14-17 illustrate the synthesis of other ketones that may beused as intermediates to prepare compounds of Formula (IB) in methodsanalogous to those described in Example 13.

Example 14 Synthesis of1-cyclopropyl-3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-one

To a solution of cyclopropyl bromide (0.120 g) in THF (0.8 mL) cooled to−70° C., a solution of tert-butyl lithium (1.7 M in pentane, 0.8 mL) wasadded dropwise over 5 minutes. The mixture was stirred at −70° C. for 30minutes. A solution of3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.29g) in THF (1 mL) was then added all at once and the mixture was stirredfor 30 minutes. The mixture was quenched with EtOH (0.3 mL) and warmedto room temperature. The mixture was diluted with EtOAc, washed withwater, dried over sodium sulfate, filtered, and evaporated to give thetitle compound as an oil (0.23 g).

Example 15 Synthesis of1-cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one

To a solution of cyclohexylmethyl bromide (0.26 g) in THF (1 mL) cooledto −70° C. under argon, tert-butyl lithium (1.7 M in pentane, 1.8 mL)was added dropwise over 5 minutes. The mixture was stirred at −70° C.for 30 minutes. A solution of3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.33g) in THF (1 mL) was added all at once and the mixture was stirred forone hour. The reaction temperature rose to approximately coming to −20°C. The reaction was quenched with EtOH (0.3 mL), and warmed to roomtemperature. The mixture was diluted with EtOAc, washed with water,dried, filtered, and evaporated. Chromatography of the residue oversilica gel (eluent: hexanes-methylene chloride gradient) gave the titlecompound as an oil (0.2 g).

Example 16 Synthesis of5-(5-fluoro-2-methoxyphenyl)-2,5-dimethylhexan-3-one

To a solution of3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.45g) in THF (2 mL) stirred under argon and cooled on dry ice/acetone wasadded isopropyl lithium (0.7M in pentane, 3 mL) over 10 minutes. Themixture was stirred for 20 minutes and quenched with EtOH (0.3 mL). Themixture was warmed to room temperature and water 1 mL was added. Theorganic phase was separated, washed, dried, filtered, and evaporated.The residue was fractionated over a short column of silica gel (eluent:hexanes-methylene chloride (1:1)) to give the product as an oil (0.40g).

Example 17 Synthesis of4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one

To a solution of3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.59g) in THF (1 mL) stirred under argon and cooled on dry ice/acetone wasadded methyl lithium (1.4 M in pentane, 2 mL) over 2 minutes. Themixture was stirred for 30 minutes and quenched with EtOH (0.3 mL). Themixture was warmed to room temperature and 1 mL of water was added. Theorganic phase was separated, washed, dried, filtered, and evaporated.The residue was fractionated over a short column of silica gel (eluent:hexanes-methylene chloride (1:1)) to give the title compound as an oil(0.36 g).

Example 18 Synthesis of4-(5-fluoro-2-methoxyphenyl)-2-(indol-2-ylmethyl)-4-methylpentan-2-ol

To a solution of 2-methylindole (130 mg) in THF (2 mL) stirred underargon cooled on dry ice/acetone was added n-butyl lithium (2M inpentane, 1.6 mL). After 2 minutes, potassium tert-butoxide (1M in THF, 2mL) was added and the mixture was allowed to warm to approximately −20°C. After 5 minutes, precipitate was noted and the mixture was cooled to−70° C. 4-(5-Fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 17)(440 mg) in THF (1.5 mL) was added all at once. The cooling bath wasremoved and the mixture was stirred for 10 minutes and then quenchedwith EtOH (0.5 mL). The mixture was diluted with EtOAc, washed withwater, dried, filtered, and evaporated. Chromatography over silica gel(EtOAc-hexanes (1:9)) gave product which solidified on trituration withhexanes-ether. The solid was recrystallized from ether-hexanes,collected by filtration and dried under vacuum to give 0.11 g of thetitle compound, m.p. 118° C.-120° C.

Example 19 Synthesis of4-(5-fluoro-2-methoxyphenyl)-2-(4,6-dimethylpyridin-2-ylmethyl)-4-methylpentan-2-ol

To a solution of 2,4,6-trimethylpyridine (0.14 g) in THF (1 mL) stirredunder argon and cooled to −70° C., tert-butyl lithium (1.7M in pentane,0.75 mL) was added dropwise over 2 minutes. After stirring for anadditional 2 minutes, 4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one(Example 17) (0.22 g) in THF (0.8 mL) was added all at once. After 5minutes, the reaction was quenched with EtOH (0.2 mL) and allowed towarm to room temperature. The mixture was diluted with EtOAc, washedwith water, dried, filtered, and evaporated. Chromatography of theresidue over silica gel (eluent: EtOAc-methylene chloride (2:98 to 8:92gradient)) gave the product as an oil (0.19 g).

Example 20 Synthesis of1-cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-2-(indol-2-ylmethyl)-4-methylpentan-2-ol

To a solution of the 2-methylindole (65 mg) in THF (1 mL) stirred underargon cooled on dry ice/acetone was added n-butyl lithium (2 M inpentane, 0.8 mL). After 2 minutes, potassium tert-butoxide (1M in THF, 1mL) was added and the mixture was allowed to warm to approximately −20°C. After 5 minutes, a precipitate was noted and the mixture was cooledto −70° C.1-Cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example15) (100 mg) in THF (1 mL) was added dropwise and the mixture wasstirred for 20 minutes at −70° C. The reaction was quenched with EtOH(0.5 mL). The mixture was diluted with EtOAc, washed with water, dried,filtered, and evaporated. Chromatography over silica gel (methylenechloride-hexanes (1:2)) gave the title compound as an oil (0.095 g).

Example 21 Synthesis of5-(5-fluoro-2-methoxyphenyl)-3-(indol-2-ylmethyl)-5-methylhexan-3-ol

To a solution of lithium diisopropylamide (2 M inTHF-hexanes-ethylbenzene, 1.0 mL) in THF 1 mL under argon cooled to −70°C. was added dropwise a solution of4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (0.44 g) in THF (1mL). The mixture was stirred for 30 minutes and then a solution ofmethyl iodide (0.28 g) in THF (0.5 mL) was added dropwise and themixture was stirred coming to room temperature overnight. The mixturewas diluted with hexanes, washed with water, dried, filtered, andevaporated. Chromatography of the residue over silica gel(hexanes-methylene chloride (gradient 1:4-1:1)) gave the desiredhexan-3-one as an oil (0.20 g).

To a solution of 2-methylindole (64 mg) in THF (1 mL) stirred underargon cooled on dry ice/acetone was added n-butyl lithium (2M inpentane, 0.8 mL). After 2 minutes, potassium tert-butoxide (1M in THF, 1mL) was added and the mixture was allowed to warm to approximately −20°C. After approximately 5 minutes, a precipitate was noted and themixture was cooled to −70° C. The hexan-3-one (100 mg) in THF (1 mL) wasadded dropwise and the mixture was stirred for 20 minutes at −70° C. Thereaction was quenched with EtOH (0.5 mL). The mixture was diluted withEtOAc, washed with water, dried, filtered, and evaporated.Chromatography over silica gel (methylene chloride-hexanes (1:2)) gavethe title compound as an oil (0.062 g).

Example 22 Synthesis of1-cyclohexyl-2-(4,6-dimethylpyridin-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

To a solution of collidine (0.113 g) in THF (1 mL) cooled to −70° C. wasadded dropwise over 3 minutes tert-butyl lithium (1.7 M in pentane, 0.55mL). The mixture was stirred for 5 minutes and then1-cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example15) (0.095 g) in THF (0.5 mL) was added dropwise. After 10 minutes at−70° C., the reaction was quenched by addition of EtOH (0.2 mL) andwarmed to room temperature. The mixture was diluted with EtOAc, washedwith water, dried over sodium sulfate, filtered, and evaporated. Theresidue was fractionated by preparative layer chromatography (developer:methylene chloride-EtOAc (99:1)) followed by preparative layerchromatography (developer: hexanes-methylene chloride-EtOH (1:1:0.01))to give the title compound as an oil (73 mg).

Examples 23 and 24 illustrate the synthesis of substituteddihydrobenzofurans. These may be converted to trifluoromethyl ketoneintermediates by the procedure described in Example 1 for4-fluoroanisole.

Example 23 Synthesis of 5-methyl-2,3-dihydrobenzofuran

To a chilled (10° C.) solution of 10 g (83 mmol) of2,3-dihydrobenzofuran in 50 mL of acetic acid, 4 mL (78 mmol) of brominein 6 mL of acetic acid was added dropwise over a 10 minute period. After1 hour, the mixture was made basic by cautiously pouring the reactionmixture into saturated/solid aqueous sodium bicarbonate solution andstirring overnight. The mixture was then extracted with three 100 mLportions of EtOAc. The combined organic layers were washed with two 50mL portions of saturated aqueous sodium bicarbonate, three 50 mLportions of brine, dried over magnesium sulfate, filtered, andconcentrated to afford a yellow oil. The oil was diluted with hexanesand passed through a pad of silica gel in a 600 mL funnel eluting withhexanes to afford a white solid which was diluted with cold (dryice-acetone) hexanes and collected by filtration to afford 4.7 g (28%)of 5-bromo-2,3-dihydrobenzofuran as a white solid, mp 45° C.-48° C. Thefiltrate was concentrated to afford 5.1 g of5-bromo-2,3-dihydrobenzofuran which was 70% pure.

To a chilled (−78° C.) solution of 5.2 g (26.12 mmol) of5-bromo-2,3-dihydrobenzofuran in anhydrous THF was added 13.4 mL (26.8mmol) of a 2.0 M solution of n-butyl lithium in pentane. After 10minutes, 4 mL (64.25 mmol) of iodomethane was added dropwise. After theaddition, the cold bath was removed and the mixture stirred at roomtemperature. After 2 hours, the mixture was diluted with 40 mL ofsaturated aqueous ammonium chloride and extracted with three 30 mLportions of EtOAc. The combined organic layers were washed with three 30mL portions of brine, dried over magnesium sulfate, filtered, andconcentrated to afford 3.7 g of a yellow oil. The oil was distilledunder vacuum (Kugelrohr) at 70° C.-80° C. to afford 1.6 g (45%) of thetitle compound which was used without further purification.

Using the procedure described in Example 1, the following ketone wasprepared:1,1,1-Trifluoro-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-one.

Example 24 Synthesis of 5-Fluoro-2,3-dihydrobenzofuran

To a solution of 25.5 g (0.212 mol) of 2,3-dihydrobenzofuran in 175 mLof acetic acid was added about one quarter of 4.5 mL (0.227 mol) of 70%aqueous nitric acid dropwise. The reaction was monitored by TLC(EtOAc-hexanes, 15:85). The mixture was warmed to 70° C. where thereaction began. The remainder of the nitric acid was then added whilemaintaining the reaction at 70° C. After 30 minutes, the reaction wascooled and poured into 1.5 L of ice water. The black solid was collectedby filtration washing with water. The solid was partitioned between 500mL of saturated aqueous sodium bicarbonate and 150 mL of EtOAc.

The aqueous layer was separated and extracted with three 150 mL portionsof EtOAc. The combined organic layers were washed with three 100 mLportions of saturated aqueous sodium bicarbonate, 100 mL of saturatedaqueous ammonium chloride, 100 mL of brine, dried over magnesiumsulfate, filtered, and concentrated to afford a red oil/solid. Themixture was dissolved in dichloromethane and passed through a pad ofsilica gel, eluting with dichloromethane, and concentrated. Theresulting red mixture was triturated with ether-hexanes (1:1) andfiltered to afford 10.5 g (29%) of 5-nitro-2,3-dihydrobenzofuran as atan solid.

To a suspension of 10.3 g (62.37 mmol) of 5-nitro-2,3-dihydrobenzofuranin 50 mL of MeOH and 10 mL of dichloromethane was added 350 mg of 10%palladium on carbon and the mixture was placed under 55 psi of hydrogengas. Hydrogen gas uptake was evident during the first 30 minutes. After18 hours, the mixture was then filtered through diatomaceous earth andconcentrated to afford 8.2 g of 2,3-dihydrobenzofuran-5-ylamine as agray solid which was used without further purification.

To a solution of 8.2 g (60.66 mmol) of 2,3-dihydrobenzofuran-5-ylaminein 250 mL of THF was added 6 mL of concentrated aqueous HCl in severalportions. To the resulting white precipitate was added 11 mL oftetrafluoroboric acid dropwise. The mixture was then chilled (−15° C.)and 4.7 g (68.12 mmol) of sodium nitrite in 20 mL of water was addeddropwise. The suspension turned deep gray, became homogenous and then aprecipitate formed. The mixture was stirred for 30 minutes at −15° C.and then the solid was collected by filtration washing with cold water,cold ethanol, and cold ether. The solid was dried by pulling vacuumthrough the filter cake to afford 9.7 g (68%) of5-diazonium-2,3-dihydrobenzofuran tetrafluoroborate salt which was usedwithout further purification.

A suspension of 9.7 g (41.46 mmol) of the above diazoniumtetrafluoroborate salt in xylenes was warmed at reflux for 1 hour. Themixture was then cooled and diluted with 200 mL of saturated aqueoussodium bicarbonate. The aqueous was separated and extracted with three50 mL portions of EtOAc. The combined organic layers were washed with 50mL of aqueous sodium bicarbonate, 50 mL of brine, dried over magnesiumsulfate, filtered, and concentrated to afford an oil. The crude oil waschromatographed on silica gel using EtOAc-hexanes (0:100, then 0.5:99.5)to afford 2.6 g (45%) of the title compound.

Using the procedure described in Example 1, the following ketone wasprepared:1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methylpentan-2-one.

Example 25 Synthesis of1,1,1-trifluoro-3-[1-(5-fluoro-2-methoxyphenyl)cyclopropyl]propan-2-one

To a chilled (−78° C.) solution of 5.2 mL (30.18 mmol) of2-bromoallyltrimethylsilane and 5.3 g (31.16 mmol) of ethyltrifluoropyruvate in 75 mL of dichloromethane was added 30 mL (30 mmol)of a 1 M solution of titanium tetrachloride in dichloromethane over a 10minute period. The cold bath was then removed and the mixture was warmedto room temperature. After 3 hours, the mixture was cautiously added to100 mL of saturated aqueous ammonium chloride and filtered throughdiatomaceous earth, washing with dichloromethane. The dichloromethanewas separated and the aqueous layer was extracted with three 50 mLportions of dichloromethane. The combined organic layers were washedwith two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mLof brine, dried over magnesium sulfate, filtered, and concentrated toafford 6.7 g (76%) of 4-bromo-2-hydroxy-2-trifluoromethylpent-4-enoicacid ethyl ester as a yellow oil which was used without furtherpurification.

A mixture of 500 mg (1.71 mmol) of4-bromo-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester, 509 mg(3 mmol) of 3-fluoro-5-methoxyphenylboronic acid and 25 mg (0.022 mmol)of tetrakis(triphenylphosphine)palladium(0) in 4 mL of toluene, 2 mL ofethanol, and 1 mL of 2 M aqueous sodium carbonate was warmed at reflux.After 24 hours, the mixture was cooled and diluted with saturatedaqueous ammonium chloride and extracted with three 10 mL portions ofEtOAc. The combined organic layers were washed with three 5 mL portionsof brine, dried over magnesium sulfate, filtered, and concentrated. Thecrude solidified upon standing and was adsorbed onto silica gel andchromatographed on silica gel using EtOAc-hexanes (0:100, then 0.5:99.5,then 1:99, then 2:98) to afford partially purified product. Triturationwith ether-hexanes removed an insoluble by product. The filtrate waschromatographed on silica gel using dichloromethane-hexanes (5:95, then1:9, then 15:85, then 2:8, then 3:7, then 4:6) to afford 280 mg (48%) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-2-trifluoromethylpent-4-enoicacid ethyl ester as an oil which solidified upon standing.

To a solution of 620 mg (1.84 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-2-trifluoromethylpent-4-enoicacid ethyl ester, 475 mg zinc copper couple, and an iodine crystal inanhydrous ether in a sealed tube warmed to 55° C. was added dropwise 500μL (6.20 mmol) of diiodomethane. The reaction was monitored by TLC indichloromethane-hexanes (1:1) or ether-hexanes (2:8). After 18 hours,the mixture was cooled, diluted with EtOAc, and filtered throughdiatomaceous earth. The filtrate was washed with three 10 mL portions of1 N aqueous HCl, 10 mL of brine, three 10 mL portions of saturatedaqueous sodium bicarbonate, dried over magnesium sulfate, filtered, andconcentrated. The crude material was adsorbed onto silica gel andchromatographed on silica gel using ether-hexanes (0:100, then 1:99,then 2:98) to afford 494 mg (76%) of3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]-2-hydroxypropionicacid ethyl ester.

To a chilled (0° C.) solution of 400 mg (1.14 mmol) of3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]-2-hydroxypropionicacid ethyl ester in 5 mL of anhydrous THF was added 98 mg (2.58 mmol) oflithium aluminum hydride in several portions. The cold bath was thenremoved and the mixture was stirred at room temperature. After 4.5hours, the mixture was cooled in an ice water bath and cautiouslyquenched with water, dried over magnesium sulfate, and filtered throughdiatomaceous earth, washing with EtOAc to afford 278 mg (78%) of titlecompound which was used without further purification. The filter cakewas partitioned between 15 mL of 1 N aqueous hydrochloric acid andextracted with three 10 mL portions of EtOAc. The combined organiclayers were washed with two 10 mL portions of 1 N aqueous hydrochloricacid, 10 mL of brine, and two 10 mL portions of saturated aqueous sodiumbicarbonate, dried over magnesium sulfate, filtered, and concentrated toafford an addition 32 mg (8.9%) of3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]propane-1,2-diol.

To a solution of 310 mg (1.01 mmol) of3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]propane-1,2-diolin 15 mL of MeOH was added 1.5 g (7.01 mmol) of sodium periodate. After7 hours, the mixture was concentrated and the residue diluted withhexanes and filtered through diatomaceous earth. The crude residue waschromatographed on silica gel using hexanes to load the sample and theneluting with EtOAc-hexanes (0:100, then 0.25:99.75, then 0.5:99.5, then1:99) to afford 200 mg of the title compound as a clear oil. Thefollowing trifluoromethyl ketones were also prepared by the method ofExample 25:

-   1,1,1-Trifluoro-3-[1-(2-trifluoromethoxyphenyl)cyclopropyl]propan-2-one;-   3-[1-(2,5-Difluorophenyl)cyclopropyl]-1,1,1-trifluoropropan-2-one;    and-   1,1,1-Trifluoro-3-[1-(4-fluorophenyl)cyclopropyl]propan-2-one.

Example 26 Synthesis of1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-one

To a round bottom flask fitted with a Dean-Stark trap was added amixture of 19.54 g (116 mmol) of 4-fluoro-2-methoxyacetophenone, 15.29mL (174 mmol) of methyl cyanoacetate, 1.42 mL (13 mmol) of benzylamine,and 6.6 mL of acetic acid in 170 mL of toluene and the mixture waswarmed to reflux. The reaction was monitored by TLC (EtOAc-hexanes,2:8). After 18 hours, the reaction was then cooled and concentrated invacuo to afford a dark, orange oil. The crude oil was distilled at 130°C. under vacuum (Kugelrohr) to remove unreacted4-fluoro-2-methoxyactophenone. The crude product was then passed througha pad of silica gel using a 10% EtOAc in a 1:1 mixture ofdichloromethane in hexanes to afford 27.64 g (95%) of2-cyano-3-(4-fluoro-2-methoxyphenyl)but-2-enoic acid methyl ester as alight orange oil which was a mixture of geometric isomers.

To a chilled (0° C.) suspension of 4.3 g (22.58 mmol) of copper (I)iodide (purified by Soxhlet extraction with THF) in 100 mL of diethylether was added 26 mL (41.60 mmol) of a 1.6 M solution of methyl lithiumin ether over a 15 minute period. After the addition, the mixturestirred for 10 min and was then cooled to −25° C. and a solution of 4.0g (15.19 mmol) of 2cyano-3-(4-fluoro-2-methoxyphenyl)but-2-enoic acidmethyl ester in 50 mL of diethyl ether was added over a 20 minuteperiod. The mixture stirred at −25° C. for 30 minutes and was thenallowed to warm to room temperature. The reaction was monitored byproton NMR. After 1.5 hours, an aliquot partitioned between EtOAc and 1N aqueous HCl indicated starting material was gone and desired productwas present. The reaction was cautiously poured into brine and thensaturated aqueous ammonium chloride was added followed by 1 N aqueousHCl and EtOAc. The mixture was filtered through diatomaceous earth andthe aqueous layer was separated and extracted with three 50 mL portionsof EtOAc. The combined organic layers were washed with 30 mL of 1 Naqueous HCl, 30 mL of brine, and three 25 mL portions of saturatedaqueous sodium bicarbonate, dried over magnesium sulfate, filtered, andconcentrated to afford 4.2 g (99%) of2-cyano-3-(4-fluoro-2-methoxyphenyl)-3-methylbutyric acid methyl ester.

A mixture of 4.2 g (15.03 mmol) of2-cyano-3-(4-fluoro-2-methoxyphenyl)-3-methylbutyric acid methyl esterand 2.5 g (42.77 mmol) of sodium chloride in 40 mL of DMSO with 2 mL ofwater was warmed to reflux. Gas evolution was clearly evident early inthe reaction. After 4 hours, the reaction was cooled and diluted with100 mL of brine and extracted with four 75 mL portions of EtOAc. Thecombined organic layers were washed with six 50 mL portions of brine,dried over magnesium sulfate, filtered, and concentrated to afford anoil which solidified under vacuum. The tan solid was triturated withhexanes and collected by filtration to afford 2.52 g (81%) of3-(4-fluoro-2-methoxyphenyl)-3-methylbutyronitrile, m.p. 80° C.-83° C.

To a chilled (−40° C.) solution of 2 g (9.65 mmol) of3-(4-fluoro-2-methoxyphenyl)-3-methylbutyronitrile in 20 mL ofdichloromethane was added 20 mL (20 mmol) of a 1 M solution ofdiisobutylaluminum hydride in dichloromethane over a 10 minute period.The mixture was then allowed to warm to room temperature. After 4 hours,the mixture was cautiously added to 1 N aqueous HCl and concentrated invacuo to remove the dichloromethane. The residue was extracted withthree 40 mL portions of EtOAc. The combined organic layers were washedwith 30 mL of 1 N aqueous HCl, two 30 mL portions of brine, 30 mL ofsaturated aqueous sodium bicarbonate, dried over magnesium sulfate,filtered, and concentrated to afford 1.89 g (93%) of3-(4-fluoro-2-methoxyphenyl)-3-methylbutyraldehyde as an oil which wasused without further purification.

To 1.89 g (8.99 mmol) of3-(4-fluoro-2-methoxyphenyl)-3-methylbutyraldehyde was added 25 mL (12.5mmol) of a 0.5 M solution of trimethyl(trifluoromethyl)silane intetrahydrofuran and 2 mL (2 mmol) of a 1 M solution oftetrabutylammonium fluoride in tetrahydrofuran was added over a 2 minuteperiod. The mixture stirred for 30 minutes and then an additional 8 mL(8 mmol) of a 1 M solution of tetrabutylammonium fluoride intetrahydrofuran was added. The mixture was then diluted with water andextracted with three 25 mL portions of EtOAc. The combined organiclayers were washed with three 20 mL portions of 1 N aqueous HCl, three20 mL portions of brine, and three 20 mL portions of saturated aqueoussodium bicarbonate, dried over magnesium sulfate, filtered, andconcentrated to afford 2.78 g of1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol as anoil. The oil was dried under high vacuum to a constant weight of 2.36 g(93%) and was used without further purification.

To a solution of 2.3 g (8.42 mmol) of1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol in 40mL of dichloromethane was added the 4.96 (11.70 mmol) of Dess-Martinperiodinane. After 1 hour, the mixture was concentrated and diluted withether-hexanes (1:9) and filtered through a pad of silica gel, washingwith 1:1 ether-hexanes. Use of a second pad of silica gel washing withEtOAc-hexanes (1:9) afforded the title compound as an oil. The productwas dried under vacuum to a constant weight of 2 g (85%).

The following trifluoromethyl ketones were also prepared by the methodof Example 26:

-   4-(3,5-Dimethoxyphenyl)-1,1,1-trifluoro-4-methylpentan-2-one;-   1,1,1-Trifluoro-4-(1-methoxynaphthalen-2-yl)-4-methylpentan-2-one;-   1,1,1-Trifluoro-4-methyl-4-naphthalen-2-ylpentan-2-one;-   1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methylpentan-2-one; and-   1,1,1-Trifluoro-4-methyl-4-(3-trifluoromethylphenyl)pentan-2-one.

Example 27 Synthesis of4-(5-bromo-4-fluoro-2-methoxyphenyl)-1,1,1-trifluoro-4-methylpentan-2-one

To a solution of 300 mg (1.078 mmol) of1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-one(Example 26) in 0.5 mL of acetic acid was added 70 μL (1.35 mmol) ofbromine. The reaction was monitored by TLC (EtOAc-hexanes (1:9)) bypartitioning an aliquot between saturated aqueous sodium bicarbonate andEtOAc. A new slightly more polar product was observed. The reaction wasmade basic with saturated aqueous sodium bicarbonate and extracted withthree 15 mL portion of EtOAc. The combined organic layers were washedwith two 10 mL portions of saturated aqueous sodium bicarbonate and 10mL of brine, dried over magnesium sulfate, filtered, and concentrated.The residue was dissolved in hexanes and passed through a pad of silicagel, eluting with EtOAc-hexanes (0.5:99.5) to afford 375 mg (97%) of thetitle compound.

The following compounds were prepared by the method of Example 27:

-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one;    and-   4-(7-Bromo-2,3-dihydrobenzofuran-5-yl)-1,1,1-trifluoro-4-methylpentan-2-one.

Example 28 Synthesis of1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol

Aluminum amalgam was prepared from aluminum foil (1.16 g, 14.4 mmol) andmercuric chloride (12 mg, catalytic amount) in dry THF (20 mL) byvigorously stirring the mixture at room temperature for 1 hour under anargon atmosphere. A solution of propargyl bromide (4.80 mL, 80 wt. % intoluene, 43.1 mmol) in dry THF (25 mL) was slowly added to a stirredsuspension maintaining a temperature of 30° C.-40° C., and afteraddition, stirring at 40° C. was continued until a dark gray solutionwas obtained (ca. 1 hour). The propargyl aluminum sesquibromide solutionwas added to a solution of the trifluoromethylketone (4.0 g, 14.4 mmol)in dry ether (150 mL) at −78° C. The reaction mixture was stirred atthis temperature for 3 hours, and then was allowed to warm to roomtemperature, at which time it was stirred for 12 hours. The reactionmixture was then poured into 20 mL of ice water and extracted with four30 mL portions of ether. The combined extracts were washed with 20 mL ofbrine, dried over magnesium sulfate, and concentrated. The residual oilwas subjected to column chromatography over silica gel to afford purepropargylated compound as an oil.

A mixture of the above acetylene intermediate (656 mg, 2.06 mmol),(4-iodopyridin-3-yl)-carbamic acid tert-butyl ester (600 mg, 1.87 mmol)(see T. A. Kelly et al., J. Org. Chem., 1995, 60, 1877),bis(triphenylphosphine)palladium(II) chloride catalyst (72 mg, 0.1 mmol)and copper (I) iodide (39 mg, 0.2 mmol) in anhydrous triethylamine (6mL) and dry DMF (1 mL) was stirred at room temperature for 20 hours. Thereaction mixture was then diluted with 50 mL of ether and washed with 20mL of aqueous saturated ammonium chloride solution and 20 mL of brine.The organic layer was dried over magnesium sulfate and concentrated invacuo. Column chromatography over silica gel with hexanes-EtOAc (5:1 to1:1) provided{4-[6-(5-fluoro-2-methoxyphenyl)-4-hydroxy-6-methyl-4-trifluoromethylhept-1-ynyl]pyridin-3-yl}carbamicacid tert-butyl ester as a foam.

The above tert-butyl ester (480 mg, 0.94 mmol) was treated with ahydrogen chloride solution (2M in ether, 15 mL) and stirred at roomtemperature for 6 hours. Then the solution was concentrated in vacuo toyield the crude amine as oil, which was crashed out with hexanes to givethe amine a yellow solid.

To the above crude amine product (742 mg, 1.81 mmol) in anhydrous1-methyl-2-pyrrolidinone (NMP) (7 mL) was added t-BuOK (449 mg, 112mmol) and the reaction mixture was stirred under an argon atmosphere atroom temperature for 24 hours. The mixture was diluted with 30 mL ofether and washed with four 10 mL portions of water, and the combinedaqueous layers were re-extracted with 20 mL of ether, while the combinedorganic layers were washed with 10 mL of brine, dried over magnesiumsulfate, and concentrated in vacuo. The residual oil was subjected tocolumn chromatography over silica gel (methylene chloride-1% to 10%MeOH) to afford1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-olas yellowish crystals.

Resolution to the (+)- and (−)-enantiomers was accomplished by chiralHPLC on a CHIRALCEL™ OD column, eluting with 15% to 25%isopropanol-hexanes.

Assessment of Biological Properties

Compounds of the invention were evaluated for binding to the steroidreceptor by a fluorescence polarization competitive binding assay.Detailed descriptions for preparation of recombinant glucocorticoidreceptor (GR) complex used in the assay is described in U.S. provisionalapplication No. 60/291,877, filed May 18, 2001, and incorporated hereinby reference in its entirety. Preparation of the tetramethyl rhodamine(TAMRA)-labeled dexamethasone probe was accomplished using a standardliterature procedure (M. Pons et al., J. Steroid Biochem., 1985, 22, pp.267-273).

A. Glucocorticoid Receptor Competitive Binding Assay

Step 1. Characterization of the Fluorescent Probe

The wavelengths for maximum excitation and emission of the fluorescentprobe should first be measured. An example of such a probe is rhodamine(TAMRA)-labeled dexamethasone.

The affinity of the probe for the steroid receptor was then determinedin a titration experiment. The fluorescence polarization value of theprobe in assay buffer was measured on an SLM-8100 fluorometer using theexcitation and emission maximum values described above. Aliquots ofexpression vector lysate were added and fluorescence polarization wasmeasured after each addition until no further change in polarizationvalue was observed. Non-linear least squares regression analysis wasused to calculate the dissociation constant of the probe from thepolarization values obtained for lysate binding to the probe.

Step 2. Screening for Inhibitors of Probe Binding

This assay uses fluorescence polarization (FP) to quantitate the abilityof test compounds to compete with tetramethyl rhodamine (TAMRA)-labeleddexamethasone for binding to a human glucocorticoid receptor (GR)complex prepared from an insect expression system. The assay buffer was:10 mM TES, 50 mM KCl, 20 mM Na₂MoO₄.2H₂O, 1.5 mM EDTA, 0.04% w/v CHAPS,10% v/v glycerol, 1 mM dithiothreitol, pH 7.4. Test compounds weredissolved to 1 mM in neat DMSO and then further diluted to 10× assayconcentration in assay buffer supplemented with 10% v/v DMSO. Testcompounds were serially diluted at 10× assay concentrations in 10%DMSO-containing buffer in 96-well polypropylene plates. Binding reactionmixtures were prepared in 96-well black Dynex microtiter plates bysequential addition of the following assay components to each well: 15μL of 10× test compound solution, 85 μL of GR-containing baculoviruslysate diluted 1:170 in assay buffer, and 50 μL of 15 nM TAMRA-labeleddexamethasone. Positive controls were reaction mixtures containing notest compound; negative controls (blanks) were reaction mixturescontaining 0.7 μM to 2 μM dexamethasone. The binding reactions wereincubated for 1 hour at room temperature and then read for fluorescencepolarization in the LJL Analyst set to 550 nm excitation and 580 nmemission, with the Rhodamine 561 dichroic mirror installed. IC₅₀ valueswere determined by iterative non-linear curve fitting of the FP signaldata to a 4-parameter logistic equation.

Compounds found to bind to the glucocorticoid receptor may be evaluatedfor binding to the progesterone receptor (PR), estrogen receptor (ER),and mineralocorticoid receptors (MR) to evaluate the compound'sselectivity for GR. The protocols for PR and MR are identical to theabove GR method, with the following exceptions: PR insect cell lysate isdiluted 1:7.1 and MR lysate diluted 1:9.4. PR probe is TAMRA-labeledmifepristone, used at a final concentration of 5 nM in the assay, andthe negative controls (blanks) were reactions containing mifepristone at0.7 μM to 2 μM.

The ER protocol is similar to the above protocols, but uses PanVera kitreceptor, fluorescein-labeled probe. The assay components are made inthe same volumes as above, to produce final assay concentrations for ERof 15 nM and ES2 probe of 1 nM. In addition, the component order ofaddition is modified from the above assays: probe is added to the platefirst, followed by receptor and test compound. The plates are read inthe LJL Analyst set to 485 nm excitation and 530 nm emission, with theFluorescein 505 dichroic mirror installed.

Compounds found to bind to the glucocorticoid receptor may be evaluatedfor dissociation of transactivation and transrepression by assays citedin the Background of the Invention (C. M. Bamberger and H. M. Schulte,Eur. J. Clin. Invest., 2000, 30 (suppl. 3) 6-9) or by the assaysdescribed below.

B. Glucocorticoid Receptor Cell Assays

1. Induction of Aromatase in Fibroblasts (Cell Assay forTransactivation)

Dexamethasone, a synthetic ligand to the glucocorticoid receptor (GR),induces expression of aromatase in human foreskin fibroblast cells. Theactivity of aromatase is measured by the conversion of testosterone toestradiol in culture media. Compounds that exhibit binding to GR areevaluated for their ability to induce aromatase activity in humanforeskin fibroblasts.

Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429, designationCCD112SK) are plated on 96 well plates at 50,000 cells per well 5 daysbefore use, in Iscove's Modified Dulbecco's Media (GibcoBRL LifeTechnologies Cat No. 12440-053) supplemented with 10% charcoal filteredFBS (Clonetech Cat No. SH30068) and Gentamycin (GibcoBRL LifeTechnologies Cat. No. 15710-064). On the day of the experiment, themedia in the wells is replaced with fresh media. Cells are treated withtest compounds to final concentrations of 10⁻⁵ M to 10⁻⁸ M, andtestosterone to a final concentration of 300 ng/mL. Each well has atotal volume of 100 μL. Samples are made in duplicates. Control wellsinclude: (a) wells that receive testosterone only, and (b) wells thatreceive testosterone plus 2 μM of dexamethasone to provide maximuminduction of aromatase. Plates are incubated at 37° C. overnight (15 to18 hours), and supernatants are harvested at the end of incubation.Estradiol in the supernatant is measured using ELISA kits for estradiol(made by ALPCO, obtained from American Laboratory Products Cat. No.020-DR-2693) according to the manufacture's instruction. The amount ofestradiol is inversely proportional to the ELISA signals in each well.The extent of aromatase induction by test compounds is expressed as arelative percentage to dexamethasone. EC₅₀ values of test compounds arederived by non-linear curve fitting.

2. Inhibition of IL-6 Production in Fibroblasts (Cell Assay forTransrepression)

Human foreskin fibroblast cells produce IL-6 in response to stimulationby pro-inflammatory cytokine IL-1. This inflammatory response, asmeasured by the production of IL-6, can be effectively inhibited bydexamethasone, a synthetic ligand to the glucocorticoid receptor (GR).Compounds that exhibit binding to GR are evaluated for their ability toinhibit IL-6 production in human foreskin fibroblasts.

Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429) are plated on96 well plates at 5,000 cells per well the day before use, in Iscove'sModified Dulbecco's Media (GibcoBRL Life Technologies Cat. No.12440-053) supplemented with 10% charcoal filtered FBS (Clonetech Cat.No. SH30068) and Gentamycin (GibcoBRL Life Technologies Cat. No.15710-064). On the next day, media in the wells is replaced with freshmedia. Cells are treated with IL-1 (rhIL-1α, R&D Systems Cat. No.200-LA) to a final concentration of 1 ng/mL, and with test compounds tofinal concentrations of 10⁻⁵ M to 10⁻⁸ M, in a total volume of 200 μLper well. Samples are done in duplicates. Background control wells donot receive test compounds or IL-1. Positive control wells receive IL-1only and represent maximum (or 100%) amount of IL-6 production. Platesare incubated at 37° C. overnight (15 to 18 hours), and supernatants areharvested at the end of incubation. IL-6 levels in the supernatants aredetermined by the ELISA kits for IL-6 (MedSystems Diagnostics GmbH,Vienna, Austria, Cat. No. BMS213TEN) according to manufacture'sinstructions. The extent of inhibition of IL-6 by test compounds isexpressed in percentage relative to positive controls. IC₅₀ values oftest compounds are derived by non-linear curve fitting.

Evaluation of agonist or antagonist activity of compounds binding to theglucocorticoid receptor may be determined by any of the assays.

3. Modulation of Tyrosine Aminotransferase (TAT) Induction in RatHepatoma Cells

Testing of compounds for agonist or antagonist activity in induction oftyrosine aminotransferase (TAT) in rat hepatoma cells.

H4-II-E-C3 cells were incubated overnight in 96 well plates (20,000cells/100 μL/well) in MEM medium containing 10% heat inactivated FBS and1% nonessential amino acids. On the next day, cells were stimulated withthe indicated concentrations of dexamethasone or test compound(dissolved in DMSO, final DMSO concentration 0.2%) for 18 hours. Controlcells were treated with 0.2% DMSO. After 18 hours, the cells were lysedin a buffer containing 0.1% Triton X-100 and the TAT activity wasmeasured in a photometric assay using tyrosine and alpha-ketoglutarateas substrates.

For measuring antagonist activity, the hepatoma cells werepre-stimulated by addition of dexamethasone (concentration ranges from3×10⁻⁹ M to 3×10⁻⁸ M) shortly before the test compound was applied tothe cells. The steroidal non-selective GR/PR antagonist mifepristone wasused as control.

4. Modulation of MMTV-Luc Induction in HeLa Cells

Testing of compounds for agonist or antagonist activity in stimulationof MMTV-(mouse mammary tumor virus) promoter in HeLa cells.

HeLa cells were stably co-transfected with the pHHLuc-plasmid containinga fragment of the MMTV-LTR (−200 to +100 relative to the transcriptionstart site) cloned in front of the luciferase gene (Norden, 1988) andthe pcDNA3.1 plasmid (Invitrogen) constitutively expressing theresistance for the selective antibiotic GENETICIN®. Clones with bestinduction of the MMTV-promoter were selected and used for furtherexperiments.

Cells were cultured overnight in DMEM medium without phenol red,supplemented with 3% CCS (charcoal treated calf serum) and thentransferred to 96 well plates (15,000 cells/100 μL/well). On the nextday, activation of the MMTV-promoter was stimulated by addition of testcompound or dexamethasone dissolved in DMSO (final concentration 0.2%).Control cells were treated with DMSO only. After 18 hours, the cellswere lysed with cell lysis reagent (Promega, Cat. No. E1531), luciferaseassay reagent (Promega, Cat. No. E1501) was added and the glowluminescence was measured using a luminometer (BMG, Offenburg).

For measuring antagonist activity, the MMTV-promoter was pre-stimulatedby adding dexamethasone (3×10⁻⁹ M to 3×10⁻⁸ M) shortly before the testcompound was applied to the cells. The steroidal non-selective GR/PRantagonist mifepristone was used as control.

5. Modulation of IL-8 Production in U937 Cells

Testing of compounds for agonist or antagonist activity in GR-mediatedinhibition of LPS-induced IL-8 secretion in U-937 cells.

U-937 cells were incubated for 2 to 4 days in RPMI1640 medium containing10% CCS (charcoal treated calf serum). The cells were transferred to 96well plates (40,000 cells/100 μL/well) and stimulated with 1 μg/mL LPS(dissolved in PBS) in the presence or absence of dexamethasone or testcompound (dissolved in DMSO, final concentration 0.2%). Control cellswere treated with 0.2% DMSO. After 18 hours, the IL-8 concentration inthe cell supernatant was measured by ELISA, using the “OptEIA human IL-8set” (Pharmingen, Cat. No. 2654KI).

For measuring antagonist activity, the LPS-induced IL-8 secretion wasinhibited by adding dexamethasone (3×10⁻⁹ M to 3×10⁻⁸ M) shortly beforethe test compound was applied to the cells. The steroidal non-selectiveGR/PR antagonist mifepristone was used as control.

6. Modulation of ICAM-Luc Expression in HeLa Cells

Testing of compounds for agonist or antagonist activity in inhibition ofTNF-alpha-induced activation of the ICAM-promoter in HeLa cells.

HeLa cells were stably co-transfected with a plasmid containing a 1.3 kbfragment of the human ICAM-promoter (−1353 to −9 relative to thetranscription start site, Ledebur and Parks, 1995) cloned in front ofthe luciferase gene and the pcDNA3.1 plasmid (Invitrogen) whichconstitutively expresses the resistance for the antibiotic GENETICIN®.Clones with best induction of the ICAM-promoter were selected and usedfor further experiments. Cells were transferred to 96 well plates(15,000 cells/100 μL/well) in DMEM medium supplemented with 3% CCS. Onthe following day the activation of the ICAM-promoter was induced byaddition of 10 ng/mL recombinant TNF-alpha (R&D System, Cat. No.210-TA). Simultaneously the cells were treated with the test compound ordexamethasone (dissolved in DMSO, final concentration 0.2%). Controlcells were treated with DMSO only. After 18 hours, the cells were lysedwith cell lysis reagent (Promega, Cat. No. E1531), luciferase assayreagent (Promega, Cat. No. E1501) was added and glow luminescence wasmeasured using a luminometer (BMG, Offenburg).

For measuring antagonist activity, the TNF-alpha-induced activation ofthe ICAM-promoter was inhibited by adding dexamethasone (3×10⁻⁹ M to3×10⁻⁸ M) shortly before the test compound was applied to the cells. Thesteroidal non-selective GR/PR antagonist mifepristone was used ascontrol.

In general, the preferred potency range in the above assays is between0.1 nM and 10 μM, the more preferred potency range is 0.1 nM to 1 μM,and the most preferred potency range is 0.1 nM to 100 nM.

Representative compounds of the invention have been tested and haveshown activity as modulators of the glucocorticoid receptor function inone or more of the above assays. For example, the following compounds ofthe invention of Formula (IA) have demonstrated potent activity in theGR binding assay:

-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(2,6-Dichloropyridin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-[3-(2,6-Dichloropyridin-4-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4-fluorophenol;-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(1H-Benzimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(quinolin-4-ylmethyl)pentan-2-ol;-   4-(2,3-dihydro-5-cyanobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-chloropyridin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(2-chloropyridin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-chloroquinolin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(2-chloroquinolin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(4-methoxyphenyl)-4-methylpentan-2-ol;-   4-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol;-   1,1,1-Trifluoro-2-(5-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-bromopyridin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-methyl-1H-benzoimidazol-2-ylmethyl)pentan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-methyl-1H-indol-2-ylmethyl)butyl]phenol;-   4-Fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-1H-indol-2-ylmethyl)-3-hydroxy-1,1-dimethylbutyl]phenol;-   1,1,1-Trifluoro-2-(6-fluoro-1H-benzoimidazol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(3-Ethyl-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-Ethyl-6-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   2-Ethyl-6-[4,4,4-trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol;-   2-(5,7-Dimethyl-1H-benzoimidazol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   2-[3-(5,7-Dimethyl-1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4-fluorophenol;-   1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(3-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-(3-trifluoromethylphenyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(7-methyl-1H-benzoimidazol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(3-trifluoromethylphenyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   5-Fluoro-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   4-(5-Bromo-4-fluoro-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-(2-Phenyl-4-methylimidazol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-(2-Phenylimidazol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-phenylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-m-tolylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-naphthalen-2-ylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-o-tolylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-p-tolylpentan-2-ol;-   4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(7-Bromo-2,3-dihydrobenzofuran-5-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(1-methoxynaphthalen-2-yl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)naphthalen-1-ol;-   1,1,1-Trifluoro-4-methyl-4-naphthalen-2-yl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(1-methoxynaphthalen-2-yl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-p-tolylpentan-2-ol;-   4-Chroman-8-yl-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(6-Bromochroman-8-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-b]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(7-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(5-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   1,1,1-Trifluoro-4-(2-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(2-methoxyphenyl)-4-methylpentan-2-ol;-   2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   4-Bromo-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-1H-indole-5-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(5,6,7,8-tetrahydroquinolin-4-ylmethyl)pentan-2-ol;-   1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-1H-indole-3-carbonitrile;-   5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methyl-4-phenylpentan-2-ol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid methyl ester;-   1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;-   2-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   5-Fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-1H-indol-2-ylmethyl)-3-hydroxy-1,1-dimethylbutyl]phenol;-   2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-thiophen-3-ylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-thiophen-3-ylpentan-2-ol;-   5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   3-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid methyl ester;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carboxylic    acid methyl ester;-   4-(2,6-Dimethylphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   3-[4,4,4-Trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbutyl]phenol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;    and-   2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile.

The following compounds of the invention of Formula (IB) havedemonstrated potent activity in the GR binding assay:

-   5-(5-Fluoro-2-methoxyphenyl)-3-(benzimidazol-2-ylmethyl)-2,2,5-trimethylhexan-3-ol;-   4-(5-Fluoro-2-methoxyphenyl)-1-fluoro-2-(indol-2-ylmethyl)-4-methylpentan-3-ol;-   1-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-(indol-2-ylmethyl)-4-methylpentan-2-ol;-   5-(5-Fluoro-2-methoxyphenyl)-3-(indol-2-ylmethyl)-2,5-dimethylhexan-3-ol;-   5-(5-Fluoro-2-methoxyphenyl)-3-(indol-2-ylmethyl)-5-methylhexan-3-ol;    and-   2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)pentan-2-ol.

In addition, the following compounds of the invention of Formula (IA)have been tested and have shown activity as potent agonists of theglucocorticoid receptor function in one or more of the above assays:

-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(2,6-Dichloropyridin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(quinolin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;-   4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-methyl-1H-indol-2-ylmethyl)butyl]phenol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-[3-(5,7-Dimethyl-1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4-fluorophenol;-   1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(3-methoxyphenyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(4-methyl-1H-indol-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-(3-trifluoromethylphenyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(3-trifluoromethylphenyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   5-Fluoro-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   4-(5-Bromo-4-fluoro-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-m-tolylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-o-tolylpentan-2-ol;-   4-(7-Bromo-2,3-dihydrobenzofuran-5-yl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;    2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(5-fluoroquinolin-4-ylmethyl)-4-methylpentan-2-ol;-   2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   1,1,1-Trifluoro-4-(2-methoxyphenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-(2-methoxyphenyl)-4-methylpentan-2-ol;-   2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-ol;-   4-(5-Bromo-2-methoxyphenyl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;-   2-(4,4,4-Tri    fluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   4-Bromo-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-quinolin-4-ylmethylbutyl)phenol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-methyl-4-phenyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl)-1H-indole-5-carbonitrile;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(5,6,7,8-tetrahydroquinolin-4-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol;-   5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   2-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyl]phenol;-   1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;-   4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;-   2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;-   2-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;    and-   2-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile.

The following compounds of the invention of Formula (IB) have beentested and have shown activity as agonists of the glucocorticoidreceptor function in one or more of the above assays:

-   2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-1-(1H-indol-2-yl)-4-methylpentan-2-ol;    and-   2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)pentan-2-ol.

The invention also provides methods of modulating the glucocorticoidreceptor function in a patient comprising administering to the patient acompound according to the invention. If the purpose of modulating theglucocorticoid receptor function in a patient is to treat adisease-state or condition, the administration preferably comprises atherapeutically or pharmaceutically effective amount of apharmaceutically acceptable compound according to the invention. If thepurpose of modulating the glucocorticoid receptor function in a patientis for a diagnostic or other purpose (e.g., to determine the patient'ssuitability for therapy or sensitivity to various sub-therapeutic dosesof the compounds according to the invention), the administrationpreferably comprises an effective amount of a compound according to theinvention, that is, the amount necessary to obtain the desired effect ordegree of modulation.

Methods of Therapeutic Use

As pointed out above, the compounds of the invention are useful inmodulating the glucocorticoid receptor function. In doing so, thesecompounds have therapeutic use in treating disease-states and conditionsmediated by the glucocorticoid receptor function or that would benefitfrom modulation of the glucocorticoid receptor function.

As the compounds of the invention modulate the glucocorticoid receptorfunction, they have very useful anti-inflammatory and antiallergic,immune-suppressive, and anti-proliferative activity and they can be usedin patients as drugs, particularly in the form of pharmaceuticalcompositions as set forth below, for the treatment of disease-states andconditions.

The agonist compounds according to the invention can be used in patientsas drugs for the treatment of the following disease-states orindications that are accompanied by inflammatory, allergic, and/orproliferative processes:

-   (i) Lung diseases: chronic, obstructive lung diseases of any    genesis, particularly bronchial asthma and chronic obstructive    pulmonary disease (COPD); adult respiratory distress syndrome    (ARDS); bronchiectasis; bronchitis of various genesis; all forms of    restrictive lung diseases, particularly allergic alveolitis; all    forms of lung edema, particularly toxic lung edema; all forms of    interstitial lung diseases of any genesis, e.g., radiation    pneumonitis; and sarcoidosis and granulomatoses, particularly Boeck    disease.-   (ii) Rheumatic diseases or autoimmune diseases or joint diseases:    all forms of rheumatic diseases, especially rheumatoid arthritis,    acute rheumatic fever, and polymyalgia rheumatica; reactive    arthritis; rheumatic soft tissue diseases; inflammatory soft tissue    diseases of other genesis; arthritic symptoms in degenerative joint    diseases (arthroses); traumatic arthritis; collagenoses of any    genesis, e.g., systemic lupus erythematosus, scleroderma,    polymyositis, dermatomyositis, Sjögren syndrome, Still disease, and    Felty syndrome;-   (iii) Allergic diseases: all forms of allergic reactions, e.g.,    angioneurotic edema, hay fever, insect bites, allergic reactions to    drugs, blood derivatives, contrast agents, etc., anaphylactic shock    (anaphylaxis), urticaria, angioneurotic edema, and contact    dermatitis;-   (iv) Vasculitis diseases: panarteritis nodosa, polyarteritis nodosa,    arteritis temporalis, Wegner granulomatosis, giant cell arthritis,    and erythema nodosum;-   (v) Dermatological diseases: atopic dermatitis, particularly in    children; psoriasis; pityriasis rubra pilaris; erythematous diseases    triggered by various noxa, e.g., rays, chemicals, burns, etc.;    bullous dermatoses; diseases of the lichenoid complex; pruritus    (e.g., of allergic genesis); seborrheic dermatitis; rosacea;    pemphigus vulgaris; erythema multiforme exudativum; balanitis;    vulvitis; hair loss, such as occurs in alopecia greata; and    cutaneous T cell lymphomas;-   (vi) Renal diseases: nephrotic syndrome; and all types of nephritis,    e.g., glomerulonephritis;-   (vii) Hepatic diseases: acute liver cell disintegration; acute    hepatitis of various genesis, e.g., viral, toxic, drug-induced; and    chronically aggressive and/or chronically intermittent hepatitis;-   (viii) Gastrointestinal diseases: inflammatory bowel diseases, e.g.,    regional enteritis (Crohn disease), colitis ulcerosa; gastritis;    peptic esophagitis (refluxoesophagitis); and gastroenteritis of    other genesis, e.g., nontropical sprue;-   (ix) Proctological diseases: anal eczema; fissures; hemorrhoids; and    idiopathic proctitis;-   (x) Eye diseases: allergic keratitis, uveitis, or iritis;    conjunctivitis; blepharitis; neuritis nervi optici; choroiditis; and    sympathetic ophthalmia;-   (xi) Diseases of the ear, nose, and throat (ENT) area: allergic    rhinitis or hay fever; otitis externa, e.g., caused by contact    eczema, infection, etc.; and otitis media;-   (xii) Neurological diseases: brain edema, particularly tumor-related    brain edema; multiple sclerosis; acute encephalomyelitis;    meningitis; acute spinal cord injury; stroke; and various forms of    seizures, e.g., nodding spasms;-   (xiii) Blood diseases: acquired hemolytic anemia; and idiopathic    thrombocytopenia;-   (xiv) Tumor diseases: acute lymphatic leukemia; malignant lymphoma;    lymphogranulomatoses; lymphosarcoma; extensive metastases,    particularly in mammary, bronchial, and prostatic carcinoma;-   (xv) Endocrine diseases: endocrine ophthalmopathy; endocrine    orbitopathia; thyrotoxic crisis; Thyroiditis de Quervain; Hashimoto    thyroiditis; Morbus Basedow; granulomatous thyroiditis; struma    lymphomatosa; and Grave disease;-   (xvi) Organ and tissue transplantations and graft-versus-host    diseases;-   (xvii) Severe states of shock, e.g., septic shock, anaphylactic    shock, and systemic inflammatory response syndrome (SIRS);-   (xviii) Substitution therapy in: congenital primary adrenal    insufficiency, e.g., adrenogenital syndrome; acquired primary    adrenal insufficiency, e.g., Addison disease, autoimmune    adrenalitis, post-infection, tumors, metastases, etc.; congenital    secondary adrenal insufficiency, e.g., congenital hypopituitarism;    and acquired secondary adrenal insufficiency, e.g., post-infection,    tumors, metastases, etc.;-   (xix) Pain of inflammatory genesis, e.g., lumbago; and-   (xx) various other disease-states or conditions including type I    diabetes (insulin-dependent diabetes), osteoarthritis,    Guillain-Barre syndrome, restenosis following percutaneous    transluminal coronary angioplasty, Alzheimer disease, acute and    chronic pain, atherosclerosis, reperfusion injury, bone resorption    diseases, congestive heart failure, myocardial infarction, thermal    injury, multiple organ injury secondary to trauma, acute purulent    meningitis, necrotizing enterocolitis and syndromes associated with    hemodialysis, leukopheresis, and granulocyte transfusion.

In addition, the compounds according to the invention can be used forthe treatment of any other disease-states or conditions not mentionedabove which have been treated, are treated, or will be treated withsynthetic glucocorticoids (see, e.g., H. J. Hatz, Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien[Glucocorticoids: Immunological Fundamentals, Pharmacology, andTherapeutic Guidelines], Stuttgart: Verlagsgesellschaft mbH, 1998, whichis hereby incorporated by reference in its entirety). Most or all of theindications (i) through (xx) mentioned above are described in detail inH. J. Hatz, Glucocorticoide: Immunologische Grundlagen, Pharmakologieund Therapierichtlinien. Furthermore, the compounds of the invention canalso be used to treat disorders other than those listed above ormentioned or discussed herein, including in the Background of theInvention.

The antagonist compounds according to the invention, whether fullantagonists or partial antagonists, can be used in patients as drugs forthe treatment of the following disease-states or indications, withoutlimitation: type II diabetes (non-insulin-dependent diabetes); obesity;cardiovascular diseases; hypertension; arteriosclerosis; neurologicaldiseases, such as psychosis and depression; adrenal and pituitarytumors; glaucoma; and Cushing syndrome based on an ACTH secreting tumorlike pituitary adenoma. In particular, the compounds of the inventionare useful for treating obesity and all disease-states and indicationsrelated to a deregulated fatty acids metabolism such as hypertension,atherosclerosis, and other cardiovascular diseases. Using the compoundsof the invention that are GR antagonists, it should be possible toantagonize both the carbohydrate metabolism and fatty acids metabolism.Thus, the antagonist compounds of the invention are useful in treatingall disease-states and conditions that involve increased carbohydrate,protein, and lipid metabolism and would include disease-states andconditions leading to catabolism like muscle frailty (as an example ofprotein metabolism).

Methods of Diagnostic Use

The compounds of the invention may also be used in diagnosticapplications and for commercial and other purposes as standards incompetitive binding assays. In such uses, the compounds of the inventionmay be used in the form of the compounds themselves or they may bemodified by attaching a radioisotope, luminescence, fluorescent label orthe like in order to obtain a radioisotope, luminescence, or fluorescentprobe, as would be known by one of skill in the art and as outlined inHandbook of Fluorescent Probes and Research Chemicals, 6th Edition, R.P. Haugland (ed.), Eugene: Molecular Probes, 1996; Fluorescence andLuminescence Probes for Biological Activity, W. T. Mason (ed.), SanDiego: Academic Press, 1993; Receptor-Ligand Interaction, A PracticalApproach, E. C. Hulme (ed.), Oxford: IRL Press, 1992, each of which ishereby incorporated by reference in their entireties.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared using procedures well known in thepharmaceutical art and comprise at least one compound of the invention.The compounds of the invention may also be administered alone or incombination with adjuvants that enhance stability of the compounds ofthe invention, facilitate administration of pharmaceutical compositionscontaining them in certain embodiments, provide increased dissolution ordispersion, increased inhibitory activity, provide adjunct therapy, andthe like. The compounds according to the invention may be used on theirown or in conjunction with other active substances according to theinvention, optionally also in conjunction with other pharmacologicallyactive substances. In general, the compounds of this invention areadministered in a therapeutically or pharmaceutically effective amount,but may be administered in lower amounts for diagnostic or otherpurposes.

In particular, the compounds of the invention are useful in combinationwith glucocorticoids or corticosteroids. As pointed out above, standardtherapy for a variety of immune and inflammatory disorders includesadministration of corticosteroids, which have the ability to suppressimmunologic and inflammatory responses. (A. P. Truhan et al., Annals ofAllergy, 1989, 62, pp. 375-391; J. D. Baxter, Hospital Practice, 1992,27, pp. 111-134; R. P. Kimberly, Curr. Opin. Rheumatol., 1992, 4, pp.325-331; M. H. Weisman, Curr. Opin. Rheumatol., 1995, 7, pp. 183-190; W.Sterry, Arch. Dermatol. Res., 1992, 284 (Suppl.), pp. S27-S29). Whiletherapeutically beneficial, however, the use of corticosteroids isassociated with a number of side effects, ranging from mild to possiblylife threatening, especially with prolonged and/or high dose steroidusage. Accordingly, methods and compositions that enable the use of alower effective dosage of corticosteroids (referred to as the “steroidsparing effect”) would be highly desirable to avoid unwanted sideeffects. The compounds of the invention provide such a steroid sparingeffect by achieving the desired therapeutic effect while allowing theuse of lower doses and less frequent administration of glucocorticoidsor corticosteroids.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted modes of administration of pharmaceutical compositions.Thus, administration can be, for example, orally, buccally (e.g.,sublingually), nasally, parenterally, topically, transdermally,vaginally, or rectally, in the form of solid, semi-solid, lyophilizedpowder, or liquid dosage forms, such as, for example, tablets,suppositories, pills, soft elastic and hard gelatin capsules, powders,solutions, suspensions, or aerosols, or the like, preferably in unitdosage forms suitable for simple administration of precise dosages. Thepharmaceutical compositions will generally include a conventionalpharmaceutical carrier or excipient and a compound of the invention asthe/an active agent, and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles,or combinations thereof. Such pharmaceutically acceptable excipients,carriers, or additives as well as methods of making pharmaceuticalcompositions for various modes or administration are well-known to thoseof skill in the art. The state of the art is evidenced, e.g., byRemington: The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook ofPharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995;Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.), AmericanPharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger, 1990; each of which is incorporated herein by reference intheir entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds ofthe invention utilized in a particular pharmaceutical formulation willbe selected (e.g., salts) that possess suitable physical characteristics(e.g., water solubility) that is required for the formulation to beefficacious.

Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of the presentinvention in a flavored base, usually sucrose, and acacia or tragacanth,and pastilles comprising the compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administrationcomprise sterile aqueous preparations of a compound of the presentinvention. These preparations are preferably administered intravenously,although administration can also be effected by means of subcutaneous,intramuscular, or intradermal injection. Injectable pharmaceuticalformulations are commonly based upon injectable sterile saline,phosphate-buffered saline, oleaginous suspensions, or other injectablecarriers known in the art and are generally rendered sterile andisotonic with the blood. The injectable pharmaceutical formulations maytherefore be provided as a sterile injectable solution or suspension ina nontoxic parenterally acceptable diluent or solvent, including1,3-butanediol, water, Ringer's solution, isotonic sodium chloridesolution, fixed oils such as synthetic mono- or diglycerides, fattyacids such as oleic acid, and the like.

Such injectable pharmaceutical formulations are formulated according tothe known art using suitable dispersing or setting agents and suspendingagents. Injectable compositions will generally contain from 0.1 to 5%w/w of a compound of the invention.

Solid dosage forms for oral administration of the compounds includecapsules, tablets, pills, powders, and granules. For such oraladministration, a pharmaceutically acceptable composition containing acompound(s) of the invention is formed by the incorporation of any ofthe normally employed excipients, such as, for example, pharmaceuticalgrades of mannitol, lactose, starch, pregelatinized starch, magnesiumstearate, sodium saccharine, talcum, cellulose ether derivatives,glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Suchsolid pharmaceutical formulations may include formulations, as arewell-known in the art, to provide prolonged or sustained delivery of thedrug to the gastrointestinal tract by any number of mechanisms, whichinclude, but are not limited to, pH sensitive release from the dosageform based on the changing pH of the small intestine, slow erosion of atablet or capsule, retention in the stomach based on the physicalproperties of the formulation, bioadhesion of the dosage form to themucosal lining of the intestinal tract, or enzymatic release of theactive drug from the dosage form.

Liquid dosage forms for oral administration of the compounds includeemulsions, microemulsions, solutions, suspensions, syrups, and elixirs,optionally containing pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike. These compositions can also contain additional adjuvants such aswetting, emulsifying, suspending, sweetening, flavoring, and perfumingagents.

Topical dosage forms of the compounds include ointments, pastes, creams,lotions, gels, powders, solutions, sprays, inhalants, eye ointments, eyeor ear drops, impregnated dressings and aerosols, and may containappropriate conventional additives such as preservatives, solvents toassist drug penetration and emollients in ointments and creams. Topicalapplication may be once or more than once per day depending upon theusual medical considerations. Furthermore, preferred compounds for thepresent invention can be administered in intranasal form via topical useof suitable intranasal vehicles. The formulations may also containcompatible conventional carriers, such as cream or ointment bases andethanol or oleyl alcohol for lotions. Such carriers may be present asfrom about 1% up to about 98% of the formulation, more usually they willform up to about 80% of the formulation.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal administration can be presented as discretepatches adapted to remain in intimate contact with the epidermis of therecipient for a prolonged period of time. To be administered in the formof a transdermal delivery system, the dosage administration will, ofcourse, be continuous rather than intermittent throughout the dosageregimen. Such patches suitably contain a compound of the invention in anoptionally buffered, aqueous solution, dissolved and/or dispersed in anadhesive, or dispersed in a polymer. A suitable concentration of theactive compound is about 1% to 35%, preferably about 3% to 15%.

For administration by inhalation, the compounds of the invention areconveniently delivered in the form of an aerosol spray from a pump spraydevice not requiring a propellant gas or from a pressurized pack or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbondioxide, or other suitable gas. In any case, the aerosol spray dosageunit may be determined by providing a valve to deliver a metered amountso that the resulting metered dose inhaler (MDI) is used to administerthe compounds of the invention in a reproducible and controlled way.Such inhaler, nebulizer, or atomizer devices are known in the prior art,for example, in PCT International Publication Nos. WO 97/12687(particularly FIG. 6 thereof, which is the basis for the commercialRESPIMAT® nebulizer); WO 94/07607; WO 97/12683; and WO 97/20590, towhich reference is hereby made and each of which is incorporated hereinby reference in their entireties.

Rectal administration can be effected utilizing unit dose suppositoriesin which the compound is admixed with low-melting water-soluble orinsoluble solids such as fats, cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights, or fatty acid esters of polyethylene glycols, or thelike. The active compound is usually a minor component, often from about0.05 to 10% by weight, with the remainder being the base component.

In all of the above pharmaceutical compositions, the compounds of theinvention are formulated with an acceptable carrier or excipient. Thecarriers or excipients used must, of course, be acceptable in the senseof being compatible with the other ingredients of the composition andmust not be deleterious to the patient. The carrier or excipient can bea solid or a liquid, or both, and is preferably formulated with thecompound of the invention as a unit-dose composition, for example, atablet, which can contain from 0.05% to 95% by weight of the activecompound. Such carriers or excipients include inert fillers or diluents,binders, lubricants, disintegrating agents, solution retardants,resorption accelerators, absorption agents, and coloring agents.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrators include starch,methyl cellulose, agar, bentonite, xanthan gum, and the like.

Generally, a therapeutically effective daily dose is from about 0.001 mgto about 15 mg/kg of body weight per day of a compound of the invention;preferably, from about 0.1 mg to about 10 mg/kg of body weight per day;and most preferably, from about 0.1 mg to about 1.5 mg/kg of body weightper day. For example, for administration to a 70 kg person, the dosagerange would be from about 0.07 mg to about 1050 mg per day of a compoundof the invention, preferably from about 7.0 mg to about 700 mg per day,and most preferably from about 7.0 mg to about 105 mg per day. Somedegree of routine dose optimization may be required to determine anoptimal dosing level and pattern.

Pharmaceutically acceptable carriers and excipients encompass all theforegoing additives and the like.

Examples of Pharmaceutical Formulations

A. TABLETS Component Amount per tablet (mg) active substance 100 lactose140 corn starch 240 polyvinylpyrrolidone 15 magnesium stearate 5 TOTAL500

The finely ground active substance, lactose, and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B. TABLETS Component Amount per tablet (mg) active substance 80 lactose55 corn starch 190 polyvinylpyrrolidone 15 magnesium stearate 2microcrystalline cellulose 35 sodium-carboxymethyl starch 23 TOTAL 400

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose, and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodium-carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C. COATED TABLETS Component Amount per tablet (mg) active substance 5lactose 30 corn starch 41.5 polyvinylpyrrolidone 3 magnesium stearate0.5 TOTAL 90

The active substance, corn starch, lactose, and polyvinylpyrrolidone arethoroughly mixed and moistened with water. The moist mass is pushedthrough a screen with a 1 mm mesh size, dried at about 45° C. and thegranules are then passed through the same screen. After the magnesiumstearate has been mixed in, convex tablet cores with a diameter of 6 mmare compressed in a tablet-making machine. The tablet cores thusproduced are coated in known manner with a covering consistingessentially of sugar and talc. The finished coated tablets are polishedwith wax.

D. CAPSULES Component Amount per capsule (mg) active substance 50 cornstarch 268.5 magnesium stearate 1.5 TOTAL 320

The substance and corn starch are mixed and moistened with water. Themoist mass is screened and dried. The dry granules are screened andmixed with magnesium stearate. The finished mixture is packed into size1 hard gelatine capsules.

E. AMPOULE SOLUTION Component Amount per ampoule active substance 50 mgsodium chloride 50 mg water for inj. 5 mL

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg, and50 mg of active substance.

F. SUPPOSITORIES Component Amount per suppository (mg) active substance50 solid fat 1650 TOTAL 1700

The hard fat is melted. At 40° C., the ground active substance ishomogeneously dispersed therein. The mixture is cooled to 38° C. andpoured into slightly chilled suppository molds.

G. METERING AEROSOL Component Amount active substance 0.005 sorbitantrioleate 0.1 monofluorotrichloromethane and to 100difluorodichloromethane (2:3)

The suspension is transferred into a conventional aerosol container witha metering valve. Preferably, 50 μL of suspension are delivered perspray. The active substance may also be metered in higher doses ifdesired (e.g., 0.02% by weight).

H. POWDER FOR INHALATION Component Amount active substance 1.0 mglactose monohydrate to 25 mg

I. POWDER FOR INHALATION Component Amount active substance 2.0 mglactose monohydrate to 25 mg

J. POWDER FOR INHALATION Component Amount active substance 1.0 mglactose monohydrate to 5 mg

K. POWDER FOR INHALATION Component Amount active substance 2.0 mglactose monohydrate to 5 mg

In Examples H, I, J, and K, the powder for inhalation is produced in theusual way by mixing the individual ingredients together.

1. A compound of Formula (IA)

wherein: R¹ is a heteroaryl group optionally substituted with one tothree substituent groups, wherein each substituent group of R¹ isindependently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅alkanoyloxy, C₁-C₅ alkanoyl, aroyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy,C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy,carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or aminowherein the nitrogen atom is optionally independently mono- ordi-substituted by C₁-C₅ alkyl or aryl; or ureido wherein either nitrogenatom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxideor sulfone, wherein each substituent group of R¹ is optionallyindependently substituted with one to three substituent groups selectedfrom methyl, methoxy, halogen, hydroxy, oxo, cyano, or amino, R² and R³are each independently hydrogen or C₁-C₅ alkyl; R⁴ is C₁-C₅ alkyl, C₂-C₅alkenyl, or C₂-C₅ alkynyl, each optionally independently substitutedwith one to three substituent groups, wherein each substituent group ofR⁴ is independently C₁-C₃ alkyl, hydroxy, halogen, amino, or oxo; and R⁵is an indolyl group optionally substituted with one to three substituentgroups, wherein each substituent group of R⁵ is independently C₁-C₅alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy,aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino,aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl,halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, nitro, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C₁-C₅ alkyl; orureido wherein either nitrogen atom is optionally independentlysubstituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atomis optionally oxidized to a sulfoxide or sulfone, wherein eachsubstituent group of R⁵ is optionally independently substituted with oneto three substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy,halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl, or a tautomer,ester, amide, or salt thereof.
 2. The compound of Formula (IA) accordingto claim 1, wherein: R¹ is thienyl, dihydrobenzofuranyl, benzofuranyl,chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl, benzothienyl,benzodioxolanyl, dihydrobenzoxazolyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, benzimidazolyl, quinolinyl, pyridinyl, pyrimidinyl, orpyrazinyl, each optionally substituted with one to three substituentgroups, wherein each substituent group of R¹ is independently C₁-C₃alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy,C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkanoyloxy, halogen,hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, orC₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone, wherein each substituent group of R¹ is optionallyindependently substituted with a substituent group selected from methyl,methoxy, halogen, hydroxy, oxo, cyano, or amino; R² and R³ are eachindependently hydrogen or C₁-C₃ alkyl; and R⁴ is CH₂; and wherein eachsubstituent group of R⁵ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl,phenyl, C₁-C₃ alkoxy, methoxycarbonyl, aminocarbonyl, C₁-C₃alkylaminocarbonyl, C₁-C₃ dialkylaminocarbonyl, heterocyclylcarbonyl,fluoro, chloro, bromo, oxo, cyano, trifluoromethyl, or C₁-C₃ alkylthiowherein the sulfur atom is optionally oxidized to a sulfoxide orsulfone, and wherein each substituent group of R⁵ is optionallyindependently substituted with a substituent group selected from methyl,methoxy, fluoro, chloro, bromo, or trifluoromethyl, or a tautomer,ester, amide, or salt thereof.
 3. The compound of Formula (IA) accordingto claim 1, wherein: R¹ is pyridyl, chromanyl, dihydrobenzofuranyl, orbenzofuranyl, each optionally substituted with one or two substituentgroups, wherein each substituent group of R¹ is independently methyl,ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl,trifluoromethoxy, or cyano; R² R³ each independently methyl; and R⁴ isCH₂; and wherein each substituent group of R⁵ is independently methyl,phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, morpholinylcarbonyl, fluoro, chloro, bromo,cyano, or trifluoromethyl, or a tautomer, ester, amide, or salt thereof.4. The compound of Formula (IA) according to claim 1, wherein R² and R³are each independently hydrogen or C₁-C₅ alkyl, or a tautomer, ester,amide, or salt thereof.
 5. The compound of Formula (IA) according toclaim 1, wherein R⁴ is CH₂, or a tautomer, ester, amide, or saltthereof.
 6. The compound of Formula (IA) according to claim 1, wherein:R¹ is dihydrobenzofuranyl or benzofuranyl, each optionally substitutedwith one to three substituent groups, wherein each substituent group ofR¹ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃alkoxy, C₂-C₃ alkenyloxy, C ₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro,or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone; and R² and R³ are each independently hydrogen orC₁-C₃ alkyl, or a tautomer, ester, amide, or salt thereof.
 7. A compoundselected from:4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-pyridin-2-ylpentan-2-ol;4-(2,3-dihydro-5-cyanobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-ol;4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)4-methylpentan-2-ol;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;and1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-thiophen-3-ylpentan-2-ol,or a tautomer, ester, amide, or salt thereof.
 8. A compound selectedfrom:4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-pyridin-2-ylpentan-2-ol;4-(2,3-dihydro-5-cyanobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-ol;4-(2,3-Dihydrobenzofuran-5-yl)-l,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(5-trifluoromethyl-1H-indol-2-ylmethyl)pentan-2-ol;and1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-thiophen-3-ylpentan-2-ol,or a tautomer, ester, amide, or salt thereof.
 9. A compound selectedfrom:4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;4-(2,3-dihydro-5-cyanobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-ol;4-(2,3-Dihydrobenzofuran-5-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile; and1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-thiophen-3-ylpentan-2-ol,or a tautomer, ester, amide, or salt thereof.
 10. A compound selectedfrom:4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;4-(2,3-dihydro-5-cyanobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-ol;4-(2,3-Dihydrobenzofuran-5-yl),1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile;4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(7-fluoro-1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile; and1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-thiophen-3-ylpentan-2-ol,or a tautomer, ester, amide, or salt thereof.
 11. A compound selectedfrom:4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(1H-indol-2-ylmethyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-2-(1H-indol-2-ylmethyl)-4-methyl-4-(5-methyl-2,3-dihydrobenzofuran-7-yl)pentan-2-ol;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H-indole-6-carbonitrile;2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-5-carbonitrile; and1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-3-carbonitrile, or a tautomer, ester, amide, or salt thereof.
 12. Apharmaceutical composition comprising an effective amount of a compoundaccording to one of claims 1 to 11, or a tautomer, ester, amide, or saltthereof, and a pharmaceutically acceptable excipient or carrier.
 13. Amethod of making a compound of Formula (IA)

where R¹, R², R³, R⁴, and R⁵ are as defined in claim 1, the methodcomprising: (a) reacting an ester of Formula (II) with a suitablereducing agent in a suitable solvent to form a diol of Formula (III)

(b) reacting the diol of Formula (III) under suitable oxidative cleavageconditions to form a ketone of Formula (IV)

(c) reacting the ketone of Formula (IV) with a suitable organometallicreagent R⁵R⁴M where M is Li or MgX and X is Cl, Br, or I, in a suitablesolvent to form the compound of Formula (IA)

(a′) reacting the trifluoroacetamide of Formula (X) with a vinylmagnesium bromide bearing R² and R³ in a suitable solvent to provide thetrifluoromethylenone of Formula (XI)

(b′) reacting the trifluoromethylenone of Formula (XI) with a suitableorganocopper reagent generated from an organometallic reagent R⁵R⁴Mwhere M is Li or MgX and a copper salt CuX, where X is Cl, Br, or I, ina suitable solvent to form the ketone of Formula (IV)

and performing step (c) as set forth above.
 14. A method of making acompound of Formula (IA)

where R¹, R², R³, R⁴, and R⁵ are as defined in claim 1, the methodcomprising: (a) reacting an ester of Formula (II) with a suitablereducing agent in a suitable solvent to form a diol of Formula (III)

(b) reacting the diol of Formula (III) under suitable oxidative cleavageconditions to form a ketone of Formula (IV)

(c) reacting the ketone of Formula (IV) with a suitable propargylatingreagent in a suitable solvent to form an alkyne of Formula (XXVI)

(d) reacting the alkyne of Formula (XXVI) with a suitable couplingpartner, such as optionally substituted and protected anilines, whereinX is I or Br, and PG is H or a suitable protecting group, in thepresence of a suitable catalyst and a suitable base in a suitablesolvent to form an alkyne of Formula (XXVII)

(e) reacting the compound of Formula (XXVII) with a suitable base in asuitable solvent to form the compound of Formula (IA)